Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000707732 | SCV000564439 | likely pathogenic | Hypertrophic cardiomyopathy | 2021-11-23 | reviewed by expert panel | curation | The NM_000257.3(MYH7):c.2791_2793delGAG (p.Glu931del) variant has been reported in at least 8 individuals with HCM (PS4_Moderate; Tesson 1998 PMID:9829907; Richard 2013 PMID:12707239; Walsh 2017 PMID:27532257; Norrish 2019 PMID:31006259; GeneDx pers. comm., Invitae pers. comm., LMM pers. comm., OMGL pers.comm.) and segregated with disease in 5 affected individuals with HCM in 1 family (PP1_Moderate; Tesson 1998 PMID:9829907). This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). This variant is a deletion of 1 amino acid at position 931 and is not predicted to alter the protein reading-frame. Given that only 1 amino acid has been deleted, the expert panel felt that adjusting to supporting evidence would be more appropriate in this case (PM4_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_ Moderate; PP1_Moderate; PM2; PM4_Supporting. |
Laboratory for Molecular Medicine, |
RCV000707732 | SCV000059478 | likely pathogenic | Hypertrophic cardiomyopathy | 2023-06-05 | criteria provided, single submitter | clinical testing | The p.Glu931del variant has been reported in at least 8 individuals with hypertrophic cardiomyopathy (HCM; Tesson 1998 PMID:9829907; Richard 2013 PMID:12707239; Walsh 2017 PMID:27532257; Norrish 2019 PMID:31006259; GeneDx pers. comm., Invitae pers. comm., LMM pers. comm., OMGL pers.comm.) and segregated with disease in 5 affected individuals (Tesson 1998 PMID:9829907). This variant was absent from large population studies (gnomAD v3.2.1, http://gnomad.broadinstitute.org). In vitro functional studies provide some evidence that this variant impacts protein function (Singh 2021 PMID: 34051236). This variant is a deletion of 1 amino acid at position 931 and is not predicted to alter the protein reading-frame. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP criteria applied: PS4_ Moderate, PP1_Moderate, PM2_Supporting, PM4_Supporting, PS3_Supporting. |
Gene |
RCV000158830 | SCV000208765 | likely pathogenic | not provided | 2019-10-24 | criteria provided, single submitter | clinical testing | In-frame deletion of one amino acid, also referred to as E930del in the published literature due to alternate nomenclature; Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar as likely pathogenic by the ClinGen Inherited Cardiomyopathy Variant Curation Expert Panel (ClinVar Variant ID 42934 ; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 9829907, 31006259, 12707239, 29300372, 27532257) |
Invitae | RCV000707732 | SCV000836841 | pathogenic | Hypertrophic cardiomyopathy | 2023-12-20 | criteria provided, single submitter | clinical testing | This variant, c.2791_2793del, results in the deletion of 1 amino acid(s) of the MYH7 protein (p.Glu931del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with hypertrophic cardiomyopathy (HCM) (PMID: 9829907, 27532257). It has also been observed to segregate with disease in related individuals. This variant is also known as Glu930 codon deletion. ClinVar contains an entry for this variant (Variation ID: 42934). This variant disrupts the p.Glu931 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15358028, 24111713, 25351510). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |