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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This version includes:
-additional clarifying notes for not applying certain evidence codes together
-updated HHT Phenotype attached document
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
Use ENG PVS1 Decision Tree (see attachments)
Modification Type:
Gene-specific,Strength
Strong
Use ENG PVS1 Decision Tree (see attachments)
Modification Type:
Gene-specific,Strength
Moderate
Use ENG PVS1 Decision Tree (see attachments)
Modification Type:
Gene-specific,Strength
Supporting
Not Applicable
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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
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.
Modification Type:
No change
Moderate
Supporting
Instructions:
No modification. Use as applicable. 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
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.
Modification Type:
Clarification,Disease-specific
Moderate
Supporting
Instructions:
See additional information in HHT phenotype document attached. Note: low-level mosaicism has been observed in parents of individuals with HHT (PMID: 29736967, PMID: 21651515, PMID: 21378382, PMID: 21415079). 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
Modification Type:
Disease-specific,Strength
Moderate
See PS3_Supporting and Instructions below.
Modification Type:
Disease-specific,Strength
Supporting
Modification Type:
Disease-specific,Strength
Instructions:
HHT assays can be used as supporting evidence and bumped up to moderate/strong criteria if multiple different functional assays are concordant. 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
4+ probands with phenotype consistent with HHT.
Modification Type:
Disease-specific
Moderate
2-3 probands with phenotype consistent with HHT.
Modification Type:
Disease-specific
Supporting
1 proband with phenotype consistent with HHT.
Modification Type:
Disease-specific
Instructions:
Variant must also meet PM2_Supporting. See HHT phenotype document in attachments for phenotype requirements. 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
Apply if variant is located in a critical residue:
Modification Type:
Gene-specific
Supporting
Instructions:
Note: If the variant falls within a PM1 region, do not use PM1 with PM5_Strong. PM1 can still be combined with PM5. Not Applicable
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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
<6 total alleles in gnomAD or <0.00004 (0.004%) in gnomAD subpopulations.
Modification Type:
Disease-specific,Strength
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:
HHT is autosomal dominant disorder.
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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
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
Modification Type:
None
Supporting
Instructions:
No modification. Use as applicable. 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
≥2 different missense changes at same codon have been determined to be likely pathogenic or pathogenic based on HHT VCEP rules.
Modification Type:
Disease-specific,Strength
Moderate
A different missense change at same codon has been determined to be likely pathogenic or pathogenic based on HHT VCEP rules.
Modification Type:
Disease-specific,Strength
Supporting
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
Supporting
Not Applicable
Comments:
De novo variants are rare in HHT. De novo variants should be confirmed not presumed for HHT.
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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
5+ meioses (1/32 likelihood)
Modification Type:
Disease-specific,Strength
Moderate
4 meioses (1/16 likelihood)
Modification Type:
Disease-specific,Strength
Supporting
3 meioses (1/8 likelihood)
Modification Type:
Disease-specific,Strength
Instructions:
See HHT phenotype document in attachments for assignment of affected/unaffected status for purpose of inclusion in cosegregation study. 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:
Does not apply to ENG (Z-score= 0.93).
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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
Modification Type:
Disease-specific
Instructions:
SpliceAI (PMID: 30661751): https://spliceailookup.broadinstitute.org/ REVEL (PMID: 27666373) 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
Patient's phenotype meets consensus clinical diagnostic (Curaçao) criteria for HHT, and sequencing and large deletion/duplication analysis was performed for both ENG and ACVRL1 with any other identified variants ruled out.
Modification Type:
Disease-specific,Strength
Supporting
Instructions:
PP4_Moderate cannot be applied to variants that meet BS1_Supporting/BS1/BA1 criteria. If PP4_Moderate can be applied to a patient, they cannot be included in proband counting (PS4). See HHT phenotype document in attachments for information regarding Curacao phenotype requirements. Not Applicable
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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 is ≥1% in general population databases (e.g. gnomAD) based on Popmax FAF.
Modification Type:
Disease-specific
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
>0.2% to <1% in general population databases (e.g. gnomAD) based on Popmax FAF, or if variant meets BS1_Supporting and has ≥2 homozygotes.
Modification Type:
Disease-specific,Strength
Moderate
Supporting
>0.08% to 0.2% (based on gnomAD Popmax FAF).
Modification Type:
Disease-specific,Strength
Instructions:
HHT is not known to be enriched in bottlenecked populations (e.g. Ashkenazi Jewish); therefore, Popmax FAF can be calculated and applied for bottlenecked populations for BS1 and BS1_Supporting criteria. 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:
Full penetrance at an early age is not observed in HHT.
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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
Supporting
Modification Type:
Disease-specific,Strength
Instructions:
Normal protein expression cannot be used as benign evidence because protein function can still be altered (e.g. pathogenic dominant negative variants). 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
Lack of segregation in affected members of a family.
Modification Type:
Clarification,Disease-specific
Moderate
Supporting
Instructions:
See HHT phenotype document in attachments for assignment of affected/unaffected status for purpose of inclusion in cosegregation study. Not Applicable
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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:
Missense variants commonly seen in HHT genes
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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
Observed in trans with a pathogenic or likely pathogenic variant based on HHT VCEP rules.
Modification Type:
Disease-specific
Instructions:
Variants must be confirmed in trans. Not Applicable
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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
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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
Modification Type:
Disease-specific
Instructions:
SpliceAI (PMID: 30661751): https://spliceailookup.broadinstitute.org/ REVEL (PMID: 27666373) 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
Apply if a likely pathogenic or pathogenic variant (based on HHT VCEP rules) is found in ACVRL1.
Modification Type:
Disease-specific
Not Applicable
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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
A synonymous or intronic variant for which SpliceAI predicts no impact to the splice consensus sequence nor the creation of a new splice site. Can be used together with BP4 evidence.
Modification Type:
Disease-specific
Instructions:
For synonymous and intronic variants: SpliceAI score ≤0.1. Note: If no causative variant is found in ENG or ACVRL1, and the patient's clinical presentation and/or family history is highly suspicious for HHT, be careful to not dismiss intronic variants or synonymous variants in the last nucleotide of the exon based on computational predictions. Example 1: ENG c.219G>A; p.Thr73= is not predicted to significantly alter splicing (SpliceAI: 0.02) and the nucleotide is weakly conserved. However, this variant was later shown to cause exon skipping (PMID: 17384219, ARUP Laboratories). Example 2: SpliceAI does not predict splicing effects for some deep intronic ACVRL1 intron 9 CT rich hotspot variants (PMID: 30244195). Therefore, variants that create a new 'AG' cryptic splice site in this region, should not be ruled out based on SpliceAI prediction alone. Not Applicable
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