{ "data": [ { "entContent": { "label": "BS1", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0090", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "SEPIO:0000325", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0222", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable with VCEP specification", "id": "0070", "instructionsToUse": "", "specificationType": [ "Disease-specific" ], "status": "approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000328", "text": "Variant has a PopMax FAF ≥0.002 (0.2%) in gnomAD.", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0223", "instructionsToUse": "", "status": "not approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000699", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0086", "instructionsToUse": "", "status": "not approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000327", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637691" }, { "entContent": { "label": "PM3", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0232", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0038", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0058", "instructionsToUse": "", "status": "not approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable with VCEP specification", "id": "007", "instructionsToUse": "", "specificationType": [ "Disease-specific" ], "status": "approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "This criterion can be used for a candidate LDLR variant observed in an individual with a homozygous FH phenotype when there is only one other pathogenic or likely pathogenic variant in LDLR (in trans), APOB or PCSK9. Caveat: variant must also meet PM2.", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0027", "instructionsToUse": "", "status": "not approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637692" }, { "entContent": { "label": "BS2", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0091", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "SEPIO:0000357", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0224", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable with VCEP specification", "id": "0069", "instructionsToUse": "", "specificationType": [ "Disease-specific" ], "status": "approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000328", "text": "Variant is identified in ≥3 heterozygous or ≥1 homozygous well-phenotyped, untreated, normolipidemic adults (unrelated).", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0098", "instructionsToUse": "", "status": "not approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000699", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0076", "instructionsToUse": "", "status": "not approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000327", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637693" }, { "entContent": { "label": "PM4", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0233", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0012", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0035", "instructionsToUse": "", "status": "not approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable with VCEP specification", "id": "009", "instructionsToUse": "", "specificationType": [ "Disease-specific" ], "status": "approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "In-frame deletion/insertions smaller than one whole exon, or in-frame whole-exon duplications not considered in any PVS1 criteria.\nCaveat: variant must also meet PM2.", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0059", "instructionsToUse": "", "status": "not approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637694" }, { "entContent": { "label": "BS3", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0226", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "SEPIO:0000325", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0225", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable with VCEP specification", "id": "0072", "instructionsToUse": "", "specificationType": [ "Disease-specific", "Strength" ], "status": "approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000328", "text": "Variant meets Level 1 benign functional study criteria. See Table 3.\n(1) Study of the whole LDLR cycle (LDLR expression/biosynthesis, LDL binding, and LDL internalization) performed in heterologous cells (with no endogenous LDLR) transfected with mutant plasmid. Assay result of >90% of wild-type activity in expression/biosynthesis, binding AND internalization.\nNote: studies of only part of the LDLR cycle are not eligible for BS3 or BS3_Supporting. ", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0100", "instructionsToUse": "", "status": "not approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0001327", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable as originally described", "id": "0085", "instructionsToUse": "", "specificationType": [ "Disease-specific", "Strength" ], "status": "approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000327", "text": "Variant meets Level 3 benign functional study criteria. See Table 3.\n(1) Study of whole LDLR cycle in a) true homozygous patient cells, with assay result of >90% of wild-type activity in biosynthesis, binding AND internalization; or in b) heterozygous patient cells with assay result of >95% of wild-type activity in biosynthesis, binding AND internalization.\n(2) Luciferase studies with transcription levels of >90% when compared to wild-type (applicable to 5’UTR/promoter variants).\n(3) RNA studies, using RNA extracted from heterozygous or homozygous patientcells, with a) aberrant transcripts quantification, where aberrant transcript is<10% of total transcript OR b) without transcript quantification where noaberrant transcript is confirmed by sequencing.\n(4) Minigene splicing assay where only wild-type transcript is present and confirmed by sequencing.\n(5) High-throughput assays as defined above; only applicable when assay canindicate the whole LDLR cycle (LDLR expression/biosynthesis, LDL binding AND internalization) is unaffected.", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637695" }, { "entContent": { "label": "PM5", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0234", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0047", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable as originally described", "id": "0056", "instructionsToUse": "", "specificationType": [ "Strength" ], "status": "approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "Missense variant at a codon with ≥2 missense variants classified pathogenic (by these guidelines), and predicts a different amino acid change.", "type": "EvidenceLineStrength" }, { "applicability": "Applicable with VCEP specification", "id": "008", "instructionsToUse": "", "specificationtype": [ "Clarification" ], "status": "approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "Missense variant at the same codon as a variant classified pathogenic (by these guidelines), and predicts a different amino acid change.", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0048", "instructionsToUse": "", "status": "not approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637696" }, { "entContent": { "label": "BP1", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0206", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "SEPIO:0000325", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0204", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0075", "instructionsToUse": "", "status": "not approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000328", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0205", "instructionsToUse": "", "status": "not approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000699", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable for this VCEP", "id": "0082", "instructionsToUse": "", "status": "approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000327", "text": "Missense variant in gene where only LOF causes disease", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637697" }, { "entContent": { "label": "BS4", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0229", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "SEPIO:0000325", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0227", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable with VCEP specification", "id": "0071", "instructionsToUse": "", "specificationType": [ "Disease-specific" ], "status": "approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000328", "text": "Lack of segregation in ≥2 index case families (unrelated), when data is available for ≥2 informative meioses in each family.\nCaveat: must be ≥1 unaffected relative (LDL-C <50th centile) who is positive for the variant.", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0228", "instructionsToUse": "", "status": "not approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000699", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0077", "instructionsToUse": "", "status": "not approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000327", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637698" }, { "entContent": { "label": "PM6", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0235", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0014", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0037", "instructionsToUse": "", "status": "not approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable with VCEP specification", "id": "0010", "instructionsToUse": "", "specificationType": [ "Clarification" ], "status": "approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "See PS2 above.", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0022", "instructionsToUse": "", "status": "not approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637699" }, { "entContent": { "label": "PS1", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0240", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0021", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable with VCEP specification", "id": "0050", "instructionsToUse": "", "specificationType": [ "Clarification" ], "status": "approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "Missense variant at the same codon as a variant classified pathogenic (by these guidelines), and predicts the same amino acid change.\nCaveat: there is no in silico predicted splicing impact for either variant.", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0046", "instructionsToUse": "", "status": "not approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0036", "instructionsToUse": "", "status": "not approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637700" }, { "entContent": { "label": "BP2", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0209", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "SEPIO:0000325", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0207", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0068", "instructionsToUse": "", "status": "not approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000328", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0208", "instructionsToUse": "", "status": "not approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000699", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable with VCEP specification", "id": "0084", "instructionsToUse": "", "specificationType": [ "Disease-specific" ], "status": "approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000327", "text": "If a FH patient with a heterozygous phenotype has a pathogenic or likely pathogenic variant in LDLR (in trans), APOB or PCSK9, BP2 is applicable to any additional LDLR variants.", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637701" }, { "entContent": { "label": "PS2", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0241", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0016", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable with VCEP specification", "id": "0051", "instructionsToUse": "", "specificationType": [ "Clarification" ], "status": "approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "Variant is de novo in a patient with the disease and no family history. Follow SVI guidance for de novo occurrences: https://clinicalgenome.org/working-groups/sequence-variant-interpretation/", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "004", "instructionsToUse": "", "status": "not approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0043", "instructionsToUse": "", "status": "not approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637702" }, { "entContent": { "label": "BP3", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0212", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "SEPIO:0000325", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0210", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0074", "instructionsToUse": "", "status": "not approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000328", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0211", "instructionsToUse": "", "status": "not approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000699", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable for this VCEP", "id": "0081", "instructionsToUse": "", "status": "approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000327", "text": "In-frame deletions/insertions in a repetitive region without a known function", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637703" }, { "entContent": { "label": "PS3", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0242", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0031", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable with VCEP specification", "id": "0052", "instructionsToUse": "", "specificationType": [ "Disease-specific", "Strength" ], "status": "approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "Variant meets Level 1 pathogenic functional study criteria. See Table 3.\n(1) Study of the whole LDLR cycle (LDLR expression/biosynthesis, LDL binding, and LDL internalization) performed in heterologous cells (with noendogenous LDLR) transfected with mutant plasmid. Assay result of <70% ofwild-type activity in either expression/biosynthesis, binding OR internalization.", "type": "EvidenceLineStrength" }, { "applicability": "Applicable as originally described", "id": "0039", "instructionsToUse": "", "specificationType": [ "Disease-specific", "Strength" ], "status": "approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "Variant meets Level 2 pathogenic functional study criteria. See Table 3.\n(1) Study of a) only part of the LDLR cycle following Level 1 methodology, or b) whole or part of the LDLR cycle in true homozygous patient cells. A variant with assay results of <70% of wild type activity in either LDLR expression/biosynthesis, LDL binding OR internalization.\n(2) RNA studies, using RNA extracted from heterozygous or true homozygous patient cells, where aberrant transcript is confirmed by sequencing and is quantified as >25% of total transcript from heterozygous cells or 50% of total transcript from homozygous cells.\n(3) Variants with two or more Level 3 functional studies (must be different assays); or any Level 3 functional study #1-4 performed by two or more independent labs with concordant results.", "type": "EvidenceLineStrength" }, { "applicability": "Applicable as originally described", "id": "0045", "instructionsToUse": "", "specificationType": [ "Disease-specific", "Strength" ], "status": "approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "Variant meets Level 3 pathogenic functional study criteria. See Table 3.\n (1) Study of LDLR cycle (whole or part) in heterozygous patient cells, with assay results of <85% of wild-type activity in either LDLR expression/biosynthesis, LDL binding OR internalization.\n (2) Luciferase studies with transcription levels of <50% compared to wild-type (applicable to 5’UTR/promoter variants).\n (3) Minigene splicing assays with <10% wild-type transcript present where anaberrant transcript from the candidate variant is confirmed by sequencing.\n (4) High-throughput assays, which include alternative microscopy assays (e.g.,Thormaehlen et al., 2015), Multiplex Assays of Variant Effect (MAVE) (e.g.,Weile & Roth, 2018) and deep mutational scanning assays, can be considered here, only if assay has been validated with a minimum of four pathogenic and four benign variant controls in LDLR. Note: % activity thresholds will be defined by the FH VCEP as more data becomes available.\n (5) RNA studies, using RNA extracted from heterozygous or homozygous patient cells, with aberrant transcript confirmed by sequencing (but without transcript quantification).", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637704" }, { "entContent": { "label": "BP4", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0215", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "SEPIO:0000325", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0213", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0066", "instructionsToUse": "", "status": "not approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000328", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0214", "instructionsToUse": "", "status": "not approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000699", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable with VCEP specification", "id": "0080", "instructionsToUse": "", "specificationType": [ "Disease-specific" ], "status": "approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000327", "text": "REVEL score ≤0.5 (missense variants), or no predicted impact to splicing using MaxEntScan (see Fig. 2 for suggested thresholds).", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637705" }, { "entContent": { "label": "PP1", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0236", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0042", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable as originally described", "id": "0023", "instructionsToUse": "", "specificationType": [ "Disease-specific", "Strength" ], "status": "approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "Variant segregates with phenotype in ≥6 informative meioses in ≥1 family. Must include ≥2 affected relatives (LDL-C >75th centile) with the variant.", "type": "EvidenceLineStrength" }, { "applicability": "Applicable as originally described", "id": "0040", "instructionsToUse": "", "specificationType": [ "Disease-specific", "Strength" ], "status": "approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "Variant segregates with phenotype in 4-5 informative meioses in ≥1 family. Must include ≥2 affected relatives (LDL-C >75th centile) with the variant.", "type": "EvidenceLineStrength" }, { "applicability": "Applicable with VCEP specification", "id": "0060", "instructionsToUse": "", "specificationType": [ "Disease-specific", "Strength" ], "status": "approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "Variant segregates with phenotype in 2-3 informative meioses in ≥1 family. Must include ≥1 affected relative (LDL-C >75th centile) with the variant.", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637706" }, { "entContent": { "label": "PS4", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0243", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0029", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable with VCEP specification", "id": "0053", "instructionsToUse": "", "specificationType": [ "Disease-specific", "Strength" ], "status": "approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "Variant is found in ≥10 unrelated FH cases (FH diagnosis met by validated clinical criteria).\nCaveat: variant must also meet PM2", "type": "EvidenceLineStrength" }, { "applicability": "Applicable as originally described", "id": "0057", "instructionsToUse": "", "specificationType": [ "Disease-specific", "Strength" ], "status": "approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "Variant is found in 6-9 unrelated FH cases (FH diagnosis made by validated clinical criteria).\nCaveat: variant must also meet PM2.", "type": "EvidenceLineStrength" }, { "applicability": "Applicable as originally described", "id": "0032", "instructionsToUse": "", "specificationType": [ "Disease-specific", "Strength" ], "status": "approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "Variant is found in 2-5 unrelated FH cases (FH diagnosis made by validated clinical criteria).\nCaveat: variant must also meet PM2.", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637707" }, { "entContent": { "label": "PVS1", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0245", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable with VCEP specification", "id": "0017", "instructionsToUse": "", "specificationType": [ "Disease-specific", "Strength" ], "status": "approved", "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "See PVS1 flow diagram (Figure 1).", "type": "EvidenceLineStrength" }, { "applicability": "Applicable as originally described", "id": "0020", "instructionsToUse": "", "specificationType": [ "Disease-specific", "Strength" ], "status": "approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "See PVS1 flow diagram (Figure 1).", "type": "EvidenceLineStrength" }, { "applicability": "Applicable as originally described", "id": "0026", "instructionsToUse": "", "specificationType": [ "Disease-specific", "Strength" ], "status": "approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "See PVS1 flow diagram (Figure 1).", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "001", "instructionsToUse": "", "status": "not approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637708" }, { "entContent": { "label": "BP5", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0218", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "SEPIO:0000325", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0216", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0073", "instructionsToUse": "", "status": "not approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000328", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0217", "instructionsToUse": "", "status": "not approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000699", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable for this VCEP", "id": "0078", "instructionsToUse": "", "status": "approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000327", "text": "Variant found in a case with an alternate molecular basis for disease", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637709" }, { "entContent": { "label": "BA1", "strengthDescriptor": [ { "applicability": "Applicable with VCEP specification", "id": "0087", "instructionsToUse": "", "specificationType": [ "Disease-specific" ], "status": "approved", "strength": "Stand Alone", "strengthSepioID": "SEPIO:0000325", "text": "Variant has a PopMax FAF ≥0.005 (0.5%) in gnomAD.", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0201", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0202", "instructionsToUse": "", "status": "not approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000328", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0203", "instructionsToUse": "", "status": "not approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000699", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0089", "instructionsToUse": "", "status": "not approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000327", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637710" }, { "entContent": { "label": "PP2", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0237", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0049", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0033", "instructionsToUse": "", "status": "not approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0034", "instructionsToUse": "", "status": "not approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0061", "instructionsToUse": "", "status": "approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637711" }, { "entContent": { "label": "PP3", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0238", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0024", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0019", "instructionsToUse": "", "status": "not approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0025", "instructionsToUse": "", "status": "not approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable with VCEP specification", "id": "0062", "instructionsToUse": "", "specificationType": [ "Disease-specific" ], "status": "approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "REVEL score ≥0.75 (missense variants), or predicted impact to splicing using MaxEntScan (see Fig. 2 for suggested thresholds).", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637712" }, { "entContent": { "label": "BP7", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0221", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "SEPIO:0000325", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0219", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0065", "instructionsToUse": "", "status": "not approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000328", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0220", "instructionsToUse": "", "status": "not approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000699", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable with VCEP specification", "id": "0079", "instructionsToUse": "", "specificationType": [ "Disease-specific" ], "status": "approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000327", "text": "Variant is synonymous.\nCaveat: variant must also meet BP4 (i.e. no predicted impact on splicing).", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637713" }, { "entContent": { "label": "PP4", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0239", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "002", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "005", "instructionsToUse": "", "status": "not approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0018", "instructionsToUse": "", "status": "not approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable with VCEP specification", "id": "0063", "instructionsToUse": "", "specificationType": [ "Disease-specific" ], "status": "approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "Any LDLR variant identified in an FH patient [diagnosis based on validated clinical criteria, e.g. Dutch Lipid Clinic Network (≥6), Simon Broome possible/definite), MEDPED], after alternative causes of high cholesterol are excluded.\nCaveat: variant must also meet PM2.", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637714" }, { "entContent": { "label": "PM1", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0230", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0015", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0028", "instructionsToUse": "", "status": "not approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable with VCEP specification", "id": "006", "instructionsToUse": "", "specificationType": [ "Disease-specific" ], "status": "approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "Missense variant located in exon 4, or a missense change in one of 60 highly conserved cysteine residues (listed in Supp. Table 4). Caveat: variant must also meet PM2.", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0054", "instructionsToUse": "", "status": "not approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637715" }, { "entContent": { "label": "PM2", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0231", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0044", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0013", "instructionsToUse": "", "status": "not approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable with VCEP specification", "id": "0011", "instructionsToUse": "", "specificationType": [ "Disease-specific" ], "status": "approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "Variant has a PopMax MAF ≤0.0002 (0.02%) in gnomAD. Consider exceptions for known founder variants.", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0030", "instructionsToUse": "", "status": "not approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637716" }, { "entContent": { "label": "BS1", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0090", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "SEPIO:0000325", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0222", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable with VCEP specification", "id": "120", "instructionsToUse": "", "specificationType": [ "Disease-specific", "Gene-specific" ], "status": "approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000328", "text": "Allele frequency is >=0.02% based on the filtering allele frequency (FAF) in ExAC provided there is no conflicting information", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0223", "instructionsToUse": "", "status": "not approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000699", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0086", "instructionsToUse": "", "status": "not approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000327", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637772" }, { "entContent": { "label": "PM3", "strengthDescriptor": [ { "applicability": "Not Applicable for this VCEP", "id": "0232", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable for this VCEP", "id": "0038", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable for this VCEP", "id": "0058", "instructionsToUse": "", "status": "not approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable for this VCEP", "id": "007", "instructionsToUse": "", "status": "not approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable for this VCEP", "id": "0027", "instructionsToUse": "", "status": "not approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637773" }, { "entContent": { "label": "BS2", "strengthDescriptor": [ { "applicability": "Not Applicable for this VCEP", "id": "0091", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "SEPIO:0000357", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable for this VCEP", "id": "0224", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable for this VCEP", "id": "0069", "instructionsToUse": "", "status": "not approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000328", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable for this VCEP", "id": "0098", "instructionsToUse": "", "status": "not approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000699", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable for this VCEP", "id": "0076", "instructionsToUse": "", "status": "not approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000327", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637774" }, { "entContent": { "label": "PM4", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0233", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0012", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0035", "instructionsToUse": "", "status": "not approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable with VCEP specification", "id": "108", "instructionsToUse": "", "specificationType": [ "Disease-specific", "Gene-specific" ], "status": "approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "Protein length changes due to in-frame deletions/insertions of any size in a non-repeat region or stop-loss variants", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0059", "instructionsToUse": "", "status": "not approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637775" }, { "entContent": { "label": "BS3", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0226", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "SEPIO:0000325", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0225", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable with VCEP specification", "id": "122", "instructionsToUse": "", "specificationType": [ "No change" ], "status": "approved", 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"status": "not approved", "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0056", "instructionsToUse": "", "status": "not approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable with VCEP specification", "id": "105", "instructionsToUse": "", "specificationType": [ "No change" ], "status": "approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "Missense change at an amino acid residue where a different missense change previously established as pathogenic", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0048", "instructionsToUse": "", "status": "not approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637777" }, { "entContent": { "label": "BP1", "strengthDescriptor": [ { "applicability": "Not Applicable for this VCEP", "id": "0206", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "SEPIO:0000325", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable for this VCEP", "id": "0204", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable for this VCEP", "id": "0075", "instructionsToUse": "", "status": "not approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000328", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable for this VCEP", "id": "0205", "instructionsToUse": "", "status": "not approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000699", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable for this VCEP", "id": "0082", "instructionsToUse": "", "status": "not approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000327", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637778" }, { "entContent": { "label": "BS4", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0229", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "SEPIO:0000325", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0227", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable with VCEP specification", "id": "121", "instructionsToUse": "", "specificationType": [ "Disease-specific", "Gene-specific" ], "status": "approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000328", "text": "Non-segregation in affected members of a family", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0228", "instructionsToUse": "", "status": "not approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000699", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0077", "instructionsToUse": "", "status": "not approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000327", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637779" }, { "entContent": { "label": "PM6", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0235", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0014", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0037", "instructionsToUse": "", "status": "not approved", "strength": "Strong", 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