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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Release notes from v1.1:
Clarifications:
- MYOC has been added to the specifications guidelines name & MONDO term for POAG has been updated
- PS2: non-applicable phenotypic categories have been removed from Table 3
- PS4/PP1: individuals with multiple VUS/LP/P variants in MYOC are not considered
- PM4: add stop-loss variants to PM4
- PM5: added strong level when 2 previously established P variants have been reported
Updates:
- PP3/PS1/PM5: added capped points for combination of PP3 and PS1 (6 points max) and PP3 and PM5 (5 points max)
- PP3/BP4: apply REVEL scores at different level of strength
- BP4/BP7: remove the use of CADD for BP4 and GERP scores for BP7, and apply BP7 to intronic/noncoding/synonymous variants if BP4 is met
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
Same amino acid change as previously established pathogenic variant
Modification Type:
Clarification
Moderate
Same amino acid change as a previously established likely pathogenic variant
Modification Type:
Clarification,Strength
Supporting
Instructions:
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
Modification Type:
Disease-specific
Moderate
Modification Type:
Disease-specific,Strength
Supporting
Modification Type:
Disease-specific,Strength
Instructions:
PS2 and PM6 have been combined under PS2. See Table 3 for point system. The proposed SVI point recommendations for “phenotype consistent with gene but not highly specific” applies to JOAG and “phenotype consistent with the gene but not highly specific and with high genetic heterogeneity” applies to 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.1
Modification Type:
Disease-specific,Gene-specific
Moderate
Assays with OddsPath >4.3 as per the SVI recommendations.1
Modification Type:
Disease-specific,Gene-specific,Strength
Supporting
Assays with OddsPath >2.1 as per the SVI recommendations.1
Modification Type:
Disease-specific,Gene-specific,Strength
Instructions:
The mechanism by which the variants cause POAG is a GoF mechanism with accumulation of insoluble aggregates inside the endoplasmic reticulum of the trabecular meshwork cells.2,3 Follow the SVI recommendations from Brnich et al. when assessing functional assays to apply PS3 toward functional evidence.1
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.
Modification Type:
Gene-specific
Moderate
≥ 6 probands from multiple independent studies.
Modification Type:
Gene-specific,Strength
Supporting
≥ 2 probands from multiple independent studies.
Modification Type:
Gene-specific,Strength
Instructions:
Case-control data for MYOC variants is limited due to control cohorts often being too small to reflect the true prevalence of variants in a true control population. Instead, the Glaucoma VCEP recommends using PS4 for counting probands from multiple independent studies using a “quasi case-control study” approach.
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.
Modification Type:
Disease-specific,Gene-specific
Instructions:
The filtering allele frequency for PM2 was set one order of magnitude lower than BS1. This is a conservative approach: some pathogenic variants are expected to be present in population databases due to POAG being a complex disease with late onset and age-related penetrance. Moreover, most MYOC pathogenic variants are absent from large 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, stop-loss variants and truncating variants involving >10% of the protein and located within the conserved olfactomedin domain (AA 246-502).
Modification Type:
Gene-specific
Supporting
In-frame del/ins, stop-loss variants and truncating variants involving ≤10% of the protein and located within the conserved olfactomedin domain (AA 246-502).
Modification Type:
Gene-specific,Strength
Instructions:
The disease mechanism for MYOC variants is GoF, not LoF.2,3 Therefore, PM4 is used instead of PVS1 for truncating variants in the olfactomedin domain. One stop-loss variant has been reported in MYOC.4 There are only four in-frame variants reported in the MYOC database. There is a lack of current data to support a benign/pathogenic classification of in-frame del/ins.5,6,7,8 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
Same residue as 2 previously established pathogenic variants (both assessed independently of PM5)
Modification Type:
Clarification,Strength
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)
Modification Type:
Clarification
Supporting
Same residue as a previously established likely pathogenic variant (assessed independently of PM5)
Modification Type:
Clarification,Strength
Instructions:
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:
Refer to PS2
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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
Modification Type:
Clarification,Strength
Moderate
≥ 5 meioses regardless of the number of families
Modification Type:
Clarification,Strength
Supporting
≥ 3 meioses regardless of the number of families
Modification Type:
Clarification
Instructions:
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
REVEL score of ≥ 0.932
Modification Type:
Clarification,Strength
Moderate
REVEL score of 0.773-0.931
Modification Type:
Clarification,Strength
Supporting
REVEL score of 0.644-0.772
Modification Type:
Clarification
Instructions:
Pejaver et al. estimated thresholds for different strength of evidence for computational predictors and recommended using one that reaches a strong level of evidence for pathogenicity and moderate for benignity.26 The Glaucoma VCEP recommended using only one in silico predictor, in line with a recent study showing a lower rate of concordance when multiple software are used.25 The Glaucoma VCEP piloted the 4 predictors recommended by Pejaver et al. (REVEL, VEST4, BayesDel2 and MutPred2) on previously established LB/B and LP/P variants by the Glaucoma VCEP. Of the 4 tools, REVEL had the highest sensitivity (PP3 was applied to 95.2% (20/21) of LP/P variants (5x at PP3, 13x at PP3_Moderate and 2x at PP3_Strong), reclassifying 5x LP variants as P) and the lowest specificity (BP4 was applied to 45.0% (9/20) of LB/B variants (5x at BP4 and 4x at BP4_Moderate), reclassifying 2x LB variants as B). MutPred2 had a sensitivity of 47.6% while VEST4 and BayesDel2 had a sensitivity of 81.0%. Of note, two variants classified as LB/B was predicted to have impact with REVEL but this was consistent across the other 3 prediction tools. Therefore the VCEP recommends using REVEL based on its ease of access, high level of accuracy toward variant pathogenicity 27 and more conservative predictions toward benign impact in the context of MYOC variants. Based on the disease mechanism (GoF), the fact that all pathogenic variants are located in the last exon of the gene and the absence of current evidence supporting splicing as having a deleterious impact, the Glaucoma VCEP does not recommend using SpliceAI for PP3. 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.
Modification Type:
Disease-specific,Gene-specific
Very Strong
Strong
Moderate
Supporting
Instructions:
The Whiffin/Ware calculator13 was used to obtain a population allele frequency threshold for BA1 using conservative figures. The prevalence of POAG in the African population, which is the highest among all populations, was used (1/24).14,15The maximum allelic contribution for the most common MYOC variant (p.Gln368Ter) was set at 2.6% using data from large disease registries (the Australian and New Zealand of Advanced Glaucoma and the Glaucoma Inheritance Study in Tasmania with data on over 3,236 individuals).16 A conservative estimate for the penetrance at 7.6% was used based on the penetrance of p.Gln368Ter in a population-based study using data from the UK biobank.17 The maximum credible allele frequency calculated was 0.007, which was rounded up to 0.01. 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.
Modification Type:
Disease-specific,Gene-specific
Moderate
Supporting
Instructions:
The Whiffin/Ware calculator was used to obtain a population allele frequency threshold for BS1 using a more realistic estimate of the penetrance.13 The prevalence of POAG and the maximum allelic contribution used were the same as for BA1. A penetrance at 56% was used based on the penetrance of p.Gln368Ter in family-based studies using data from the Australian and New Zealand of Advanced Glaucoma and the Glaucoma Inheritance Study in Tasmania.17 The maximum credible allele frequency calculated was 0.001. An exemption was applied to p.Gln368Ter. MYOC p.Gln368Ter is a well-established pathogenic variant but displays incomplete penetrance. Its allele frequency in gnomAD is 0.001588 in European Non-Finnish, 0.003344 in European Finnish, and is 0.0025 in the UKBB. Evidence supports a European founder effect.18 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.
Modification Type:
Gene-specific,Strength
Supporting
Applies to variants showing solubility or secretion in functional assays for studies with OddsPath <0.48 as per the SVI recommendations.
Modification Type:
Gene-specific,Strength
Instructions:
BS3 at a Moderate or Supporting level applies to variants showing solubility or secretion in functional assays for studies with OddsPath as per the published SVI recommendations.1
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
REVEL score of ≤ 0.016
Modification Type:
Clarification,Strength
Moderate
REVEL score of 0.017-0.183
Modification Type:
Clarification,Strength
Supporting
Modification Type:
Clarification
Instructions:
Similar to PP3, The Glaucoma VCEP decided to follow the SVI recommendations to apply the REVEL thresholds calculated for the different levels of evidence.10 MYOC which only has 3 exons, one transcript and for which splicing is not known to vary. Based on the disease mechanism and the absence of current evidence supporting pathogenicity of intronic/noncoding variants, the Glaucoma VCEP agreed to apply BP4 to noncoding variants using SpliceAI. 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
Apply to intronic/noncoding and synonymous (silent) exonic variants if BP4 is met
Modification Type:
Clarification
Not Applicable
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