Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000559337 | SCV001842669 | uncertain significance | Hypertrophic cardiomyopathy | 2021-03-22 | reviewed by expert panel | curation | The c.3337G>A (p.Ala1113Thr) variant in MYH7 has been identified in 6 individuals with HCM (PS4_Moderate; GeneDx pers. comm.; Invitae pers. comm.; OMGL pers. comm.). This variant was absent from large population studies (PM2; http://gnomad.broadinstitute.org, v.2.1.1). Computational prediction tools and conservation analysis were mixed about the potential impact of this variant. In summary, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate; PM2 |
Gene |
RCV000158603 | SCV000208538 | uncertain significance | not provided | 2023-02-13 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 34542152) |
Invitae | RCV000559337 | SCV000623695 | likely pathogenic | Hypertrophic cardiomyopathy | 2023-10-04 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1113 of the MYH7 protein (p.Ala1113Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of hypertrophic cardiomyopathy (Invitae). ClinVar contains an entry for this variant (Variation ID: 36638). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000625702 | SCV000696348 | uncertain significance | not specified | 2016-06-02 | criteria provided, single submitter | clinical testing | Variant summary: The c.3337G>A (p.Ala1113Thr) in MYH7 gene is a missense change that involves a conserved nucleotide and 4/5 in silico tools predict deleterious outcome. The variant is absent from the control population dataset of ExAC. The variant of interest has been reported as Likely Pathogenic by reputable database/clinical laboratory. The variant was identified in a large family where several carriers were unaffected, one HCM individual carried the c.3337G>A in compound heterozygocity with known pathogenic variant c.1988G>A, and one carrier had a SCD at 48. Since most of the carriers of the variant of interest did not have features of HCM and a family history suggests a presence of a hereditary arrhythmia, which could have explain SCD in one carrier, additional clinical, segregation and population data needed to classify this variant with confidence. Taking together, the variant was classified as VUS. |