ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.3337G>A (p.Ala1113Thr)

gnomAD frequency: 0.00001  dbSNP: rs193922388
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel 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;, 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
GeneDx 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, LabCorp 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.
All of Us Research Program, National Institutes of Health RCV003996130 SCV004819852 uncertain significance Cardiomyopathy 2023-12-13 criteria provided, single submitter clinical testing This missense variant replaces alanine with threonine at codon 1113 of the MYH7 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MYH7-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics RCV004018689 SCV004943790 uncertain significance Cardiovascular phenotype 2021-08-18 criteria provided, single submitter clinical testing The c.3337G>A (p.A1113T) alteration is located in exon 27 (coding exon 25) of the MYH7 gene. This alteration results from a G to A substitution at nucleotide position 3337, causing the alanine (A) at amino acid position 1113 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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