Criteria Specification (CSpec) Registry is intended to provide access to the Criteria Specifications used and applied by ClinGen Variant Curation Expert Panels and biocurators in the classification of variants.
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Added MYOC HGNC ID, Replaced disease identifiers Primary open-angle glaucoma (POAG) and juvenile onset open-angle glaucoma (JOAG) (MIM: 137750) with primary open angle glaucoma (MONDO:0007665) and juvenile open angle glaucoma (MONDO:0020367).
Criteria & Strength Specifications
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PVS1 | ||||
Original ACMG Summary
Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
Caveats: • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7). • Use caution interpreting LOF variants at the extreme 3’ end of a gene. • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact. • Use caution in the presence of multiple transcripts. Stand Alone
Very Strong
Strong
Moderate
Supporting
Not Applicable
Comments:
MYOC variants cause JOAG/POAG through a gain of function (GoF) disease mechanism and not loss of function (LoF). Truncating variants in exon 3 are expected to be pathogenic because they escape nonsense-mediated decay.
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PS1 | ||||
Original ACMG Summary
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
Example: Val->Leu caused by either G>C or G>T in the same codon. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level. Stand Alone
Very Strong
Strong
Moderate
Same amino acid change as a previously established likely pathogenic variant
Supporting
Not Applicable
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PS2 | ||||
Original ACMG Summary
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity. Stand Alone
Very Strong
Strong
≥2 confirmed de novo in JOAG. Use the proposed SVI point recommendations for “phenotype consistent with gene but not highly specific” for JOAG.
Moderate
≥2 confirmed de novo in POAG or 1 confirmed de novo in JOAG Use proposed SVI point recommendations for “phenotype consistent with the gene but not highly specific and with high genetic heterogeneity” for POAG and “phenotype consistent with gene but not highly specific” for JOAG.
Supporting
1 confirmed de novo in POAG. Use proposed SVI point recommendations for “phenotype consistent with the gene but not highly specific and with high genetic heterogeneity” for POAG.
Not Applicable
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PS3 | ||||
Original ACMG Summary
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established. Stand Alone
Very Strong
Strong
Assays with OddsPath >18.7 as per the SVI recommendations.
Moderate
Assays with OddsPath >4.3 as per the SVI recommendations
Supporting
Assays with OddsPath >2.1 as per the SVI recommendations.
Not Applicable
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PS4 | ||||
Original ACMG Summary
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance. Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence. Stand Alone
Very Strong
Strong
≥ 15 probands from multiple independent studies.
Moderate
≥ 6 probands from multiple independent studies.
Supporting
≥ 2 probands from multiple independent studies.
Not Applicable
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PM1 | ||||
Original ACMG Summary
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
Stand Alone
Very Strong
Strong
Moderate
Supporting
Not Applicable
Comments:
MYOC has no mutational hot spot and benign variants are present though the well-characterised olfactomedin domain in exon 3.
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PM2 | ||||
Original ACMG Summary
Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
Caveat: Population data for indels may be poorly called by next generation sequencing. Stand Alone
Very Strong
Strong
Moderate
Supporting
Allele frequency ≤ 0.0001 in population databases.
Not Applicable
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PM3 | ||||
Original ACMG Summary
For recessive disorders, detected in trans with a pathogenic variant
Note: This requires testing of parents (or offspring) to determine phase. Stand Alone
Very Strong
Strong
Moderate
Supporting
Not Applicable
Comments:
MYOC variants have an autosomal dominant mode of inheritance.
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PM4 | ||||
Original ACMG Summary
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
Stand Alone
Very Strong
Strong
Moderate
In-frame del/ins and truncating variants involving >10% of the protein and located within the conserved olfactomedin domain (AA 246-502). Supporting
In-frame del/ins and truncating variants involving ≤10% of the protein and located within the conserved olfactomedin domain (AA 246-502). Not Applicable
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PM5 | ||||
Original ACMG Summary
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
Example: Arg156His is pathogenic; now you observe Arg156Cys. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level. Stand Alone
Very Strong
Strong
Moderate
Same residue as a previously established pathogenic variant (assessed independently of PM5) or 2 previously established likely pathogenic variants (both assessed independently of PM5)
Supporting
Same residue as a previously established likely pathogenic variant (assessed independently of PM5).
Not Applicable
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PM6 | ||||
Original ACMG Summary
Assumed de novo, but without confirmation of paternity and maternity.
Stand Alone
Very Strong
Strong
Moderate
≥2 assumed de novo in JOAG. Use proposed SVI point recommendations for “phenotype consistent with gene but not highly specific” for JOAG.
Supporting
≥2 assumed de novo in POAG or 1 assumed de novo in JOAG Use proposed SVI point recommendations for “phenotype consistent with the gene but not highly specific and with high genetic heterogeneity” for POAG and “phenotype consistent with gene but not highly specific” for JOAG.
Not Applicable
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PP1 | ||||
Original ACMG Summary
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
Note: May be used as stronger evidence with increasing segregation data. Stand Alone
Very Strong
Strong
≥7 meioses in >1 family.
Moderate
≥ 5 meioses.
Supporting
≥ 3 meioses.
Not Applicable
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PP2 | ||||
Original ACMG Summary
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
Stand Alone
Very Strong
Strong
Moderate
Supporting
Not Applicable
Comments:
Although pathogenic missense variants are common in MYOC, the gene also has a significant amount of benign missense variants as shown by the missense constraint z score in gnomAD (z = 0.52) supporting tolerance to variation.
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PP3 | ||||
Original ACMG Summary
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant. Stand Alone
Very Strong
Strong
Moderate
Supporting
Applies to missense variants with a REVEL score of ≥ 0.7. Not Applicable
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PP4 | ||||
Original ACMG Summary
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
Stand Alone
Very Strong
Strong
Moderate
Supporting
Not Applicable
Comments:
The phenotype associated with MYOC variants is not highly specific and there is genetic heterogeneity.
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PP5 | ||||
Original ACMG Summary
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
Not Applicable
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
PubMed : 29543229
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BA1 | ||||
Original ACMG Summary
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
Stand Alone
Allele frequency ≥ 0.01 in population databases.
Very Strong
Strong
Moderate
Supporting
Not Applicable
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BS1 | ||||
Original ACMG Summary
Allele frequency is greater than expected for disorder.
Stand Alone
Very Strong
Strong
Allele frequency ≥ 0.001 in population databases.
Moderate
Supporting
Not Applicable
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BS2 | ||||
Original ACMG Summary
Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.
Stand Alone
Very Strong
Strong
Moderate
Supporting
Not Applicable
Comments:
MYOC variants have an incomplete penetrance and late age of onset.
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BS3 | ||||
Original ACMG Summary
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
Stand Alone
Very Strong
Strong
Moderate
Applies to variants showing solubility or secretion in functional assays for studies with OddsPath <0.23 as per the SVI recommendations.
Supporting
Applies to variants showing solubility or secretion in functional assays for studies with OddsPath <0.48 as per the SVI recommendations.
Not Applicable
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BS4 | ||||
Original ACMG Summary
Lack of segregation in affected members of a family.
Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation. Stand Alone
Very Strong
Strong
Moderate
Supporting
Not Applicable
Comments:
The presence of phenocopies, the reduced age-related penetrance and the possibility that more than one pathogenic variant can contribute to the phenotype observed in families make non-segregation difficult to assess in the context of MYOC and POAG.
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BP1 | ||||
Original ACMG Summary
Missense variant in a gene for which primarily truncating variants are known to cause disease.
Stand Alone
Very Strong
Strong
Moderate
Supporting
Not Applicable
Comments:
Both truncating and missense MYOC variants are causative.
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BP2 | ||||
Original ACMG Summary
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
Stand Alone
Very Strong
Strong
Moderate
Supporting
Not Applicable
Comments:
Biallelic variants (either compound heterozygotes or homozygotes) have been reported (with variable phenotype) and are not incompatible with life. Two missense variants in cis could act synergistically or the effect of a variant occurring after a truncating variant may not be predicted.
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BP3 | ||||
Original ACMG Summary
In frame-deletions/insertions in a repetitive region without a known function.
Stand Alone
Very Strong
Strong
Moderate
Supporting
Not Applicable
Comments:
MYOC does not have a repetitive region without a known function.
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BP4 | ||||
Original ACMG Summary
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant. Stand Alone
Very Strong
Strong
Moderate
Supporting
Applies to:
Not Applicable
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BP5 | ||||
Original ACMG Summary
Variant found in a case with an alternate molecular basis for disease.
Stand Alone
Very Strong
Strong
Moderate
Supporting
Not Applicable
Comments:
Multiple molecular diagnoses are possible and variants in different genes could have an additive effect.
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BP6 | ||||
Original ACMG Summary
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
Not Applicable
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
PubMed : 29543229
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BP7 | ||||
Original ACMG Summary
A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
Stand Alone
Very Strong
Strong
Moderate
Supporting
Applies to synonymous variants or noncoding variants with no impact on splicing (SpliceAI ≤ 0.2) and GERP <0 for conservation. Not Applicable
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