Criteria Specification Registry

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Criteria Specification

ClinGen Glaucoma Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MYOC Version 2.0.0

Version : 2.0.0 Release Notes :

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

Glaucoma VCEP

Released

12/12/2024

05:23:40

Rules for MYOC

Gene: MYOC (HGNC:7610) HGNC Name: myocilin Transcripts: NM_000261.1 Disease: open-angle glaucoma (MONDO:0005338) Mode of Inheritance: Autosomal dominant inheritance

Criteria & Strength Specifications
PVS1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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.
PS1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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: The novel change must not affect splicing (SpliceAI ≤ 0.2) The combination of PP3 and PS1 should not be higher than 6 points Not Applicable
PS2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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 Modification Type: Disease-specific Moderate ≥2 confirmed de novo in POAG Or 1 confirmed de novo in JOAG Or ≥2 assumed de novo in JOAG Modification Type: Disease-specific,Strength Supporting 1 confirmed de novo in POAG Or ≥2 assumed de novo in POAG Or 1 assumed de novo in JOAG 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. Both maternity and paternity need to be proven for confirmed de novo variants. Parents need to be clinically assessed and not have a diagnosis of glaucoma (If a parent has suspicious signs of glaucoma, the age and the severity of the symptoms should be taken into account before applying criteria). Not Applicable
PS3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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 Applies to the following functional studies: solubility or secretion assays OR animal models that replicate the glaucoma phenotype. PS3 should only be applied if the assay includes both negative and positive controls and includes technical and/or biological replicates. If multiple results from functional assays are available for a single variant, then the evidence from the assay that is best validated should apply. Controls from the same general class of assay can be combined to calculate the odds of pathogenicity (OddsPath) as per the published SVI recommendations.¹ If results from different assays are conflicting for a single variant, then the level of validation of each assay should be considered to decide whether the results from one assay can override the results from another. Not Applicable
PS4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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. Probands need to be clinically assessed and have JOAG or POAG PM2 needs to be met (due to incomplete penetrance, late age of onset of glaucoma and the rate of undiagnosed glaucoma in the general population, pathogenic variants may be present in population databases) Individuals with multiple MYOC VUS/LP/P variants cannot be considered as evidence of either variant Not Applicable
PM1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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.
PM2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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 highest allele frequency in population databases should be used. Only applies to populations of ≥ 10,000 alleles. PM2 should be used at a Supporting level as per the SVI recommendations. 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
PM3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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.
PM4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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
PM5 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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: The novel change must not affect splicing (SpliceAI ≤ 0.2) and must meet PP3 The novel change must have a Grantham score equal or greater than the previously established pathogenic or likely pathogenic variant The combination of PP3 and PM5 should not be higher than 5 points Not Applicable
PM6 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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
PP1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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: BA1 and BS1 must not be met. Multiple families are jointly considered by adding the informative meioses across families according to Kelly et al.⁹ Only genotype positive/phenotype positive and obligate carriers/phenotype positive individuals should be counted as segregations. Individuals who are genotype positive/phenotype negative and individuals who are genotype negative/phenotype negative should not be counted Phenotype positive need to be clinically assessed and either have a diagnosis of glaucoma or suspicious signs of glaucoma. Do not apply Strong level of evidence if the variant is present in a single family due to risk of other variant in linkage disequilibrium Not Applicable
PP2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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.
PP3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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: The combination of PP3 and PM5 should not be higher than 5 points, and the combination of PP3 and PS1 should not be higher than 6 points. 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
PP4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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.
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
BA1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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 highest allele frequency in population databases should be used. Variant must be present in ≥ 5 alleles in any validated general continental population dataset of at least 2,000 observed alleles. 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
BS1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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 highest allele frequency in population databases should be used. Variant must be present in ≥ 5 alleles in any validated general continental population dataset of at least 2,000 observed alleles. Does not apply to p.Gln368Ter. 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
BS2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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.
BS3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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 Only apply if the assay includes both negative and positive controls and includes technical and/or biological replicates. If multiple results from functional assays are available for a single variant, then the evidence from the assay that is best validated should apply. Controls from the same general class of assay can be combined to calculate the odds of pathogenicity (OddsPath) as per the published SVI recommendations.¹ If results from different assays are conflicting for a single variant, then the level of validation of each assay should be considered to decide whether the results from one assay can override the results from another. Not Applicable
BS4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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.
BP1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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.
BP2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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.
BP3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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.
BP4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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 For missense variants: REVEL score of 0.184-0.290 For all other variants located outside of donor/acceptor ±1,2 dinucleotide positions, when splicing assay is not available: SpliceAI ≤ 0.1 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
BP5 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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.
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
BP7 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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

Rules for Combining Criteria

Pathogenic

≥ 2 Strong (PS1, PS2, PS3, PS4, PM5_Strong, PP1_Strong, PP3_Strong)

1 Strong (PS1, PS2, PS3, PS4, PM5_Strong, PP1_Strong, PP3_Strong) AND ≥ 3 Moderate (PS1_Moderate, PS2_Moderate, PS3_Moderate, PS4_Moderate, PM4, PM5, PP1_Moderate, PP3_Moderate)

1 Strong (PS1, PS2, PS3, PS4, PM5_Strong, PP1_Strong, PP3_Strong) AND 2 Moderate (PS1_Moderate, PS2_Moderate, PS3_Moderate, PS4_Moderate, PM4, PM5, PP1_Moderate, PP3_Moderate) AND ≥ 2 Supporting (PS2_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM4_Supporting, PM5_Supporting, PP1, PP3)

1 Strong (PS1, PS2, PS3, PS4, PM5_Strong, PP1_Strong, PP3_Strong) AND 1 Moderate (PS1_Moderate, PS2_Moderate, PS3_Moderate, PS4_Moderate, PM4, PM5, PP1_Moderate, PP3_Moderate) AND ≥ 4 Supporting (PS2_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM4_Supporting, PM5_Supporting, PP1, PP3)

Likely Pathogenic

1 Strong (PS1, PS2, PS3, PS4, PM5_Strong, PP1_Strong, PP3_Strong) AND 1 Moderate (PS1_Moderate, PS2_Moderate, PS3_Moderate, PS4_Moderate, PM4, PM5, PP1_Moderate, PP3_Moderate)

1 Strong (PS1, PS2, PS3, PS4, PM5_Strong, PP1_Strong, PP3_Strong) AND ≥ 2 Supporting (PS2_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM4_Supporting, PM5_Supporting, PP1, PP3)

≥ 3 Moderate (PS1_Moderate, PS2_Moderate, PS3_Moderate, PS4_Moderate, PM4, PM5, PP1_Moderate, PP3_Moderate)

2 Moderate (PS1_Moderate, PS2_Moderate, PS3_Moderate, PS4_Moderate, PM4, PM5, PP1_Moderate, PP3_Moderate) AND ≥ 2 Supporting (PS2_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM4_Supporting, PM5_Supporting, PP1, PP3)

1 Moderate (PS1_Moderate, PS2_Moderate, PS3_Moderate, PS4_Moderate, PM4, PM5, PP1_Moderate, PP3_Moderate) AND ≥ 4 Supporting (PS2_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM4_Supporting, PM5_Supporting, PP1, PP3)

1 Strong (PS1, PS2, PS3, PS4, PM5_Strong, PP1_Strong, PP3_Strong) AND 2 Moderate (PS1_Moderate, PS2_Moderate, PS3_Moderate, PS4_Moderate, PM4, PM5, PP1_Moderate, PP3_Moderate)

Benign

≥ 2 Strong (BS1, BP4_Strong)

1 Stand Alone (BA1)

Likely Benign

1 Strong (BS1, BP4_Strong) AND 1 Supporting (BS3_Supporting, BP4, BP7)

≥ 2 Supporting (BS3_Supporting, BP4, BP7)

Files & Images

Table 2: Point-based variant classification categories (adapted from Tavtigian et al 2020)

Table 3: Point system for PS2

Table 1: Point Values for strength of evidence categories (adapted from Tavtigian et al. 2020)

References

1. Brnich SE Abou Tayoun AN et al. Recommendations for application of the functional evidence PS3/BS3 criterion using the ACMG/AMP sequence variant interpretation framework. Genome Med (2019) 12 (1) p. 3. 10.1186/s13073-019-0690-2 31892348

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