ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2632G>T (p.Val878Leu)

dbSNP: rs730880751
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000707167 SCV000836252 pathogenic Hypertrophic cardiomyopathy 2022-05-01 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). ClinVar contains an entry for this variant (Variation ID: 582966). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 31735781; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 878 of the MYH7 protein (p.Val878Leu).
GeneDx RCV001559101 SCV001781178 likely pathogenic not provided 2021-05-20 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar (ClinVar Variant ID# 582966; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 31735781)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV001798968 SCV002042280 pathogenic Cardiomyopathy 2025-02-13 criteria provided, single submitter clinical testing The c.2632G>T variant causes an amino acid substitution, which replaces valine with leucine at position 878. It has not been reported in control populations in the Genome Aggregation Database (gnomAD). It has been previously reported in at least 2 apparently unrelated individuals and families with hypertrophic cardiomyopathy (PMID 31735781, CHEO internal data, ClinVar). This variant was reported to segregate with disease in one family (PMID 31735781). Different missense variants impacting the valine 878 residue (c.2632G>A, p.Val878Met; c.2633T>G, p.Val878Gly; c.2633T>C, p.Val878Ala) have been reported in individuals with hypertrophic cardiomyopathy in the literature (PMID 20031602, 20624503, 25132132). This variant is located within the head region (codons 181-937) of the Myosin-7 protein (NM_000257.2; NP_000248.2), where MYH7 pathogenic variants are significantly clustered (PMID 29300372). The Val878 residue is highly conserved across evolutionarily distant species. In silico analysis programs (SIFT, PolyPhen-2, Mutation Taster) predict this variant to have an impact on the protein function. This variant is listed in ClinVar (VCV000582966). Based on the above information, we categorize this variant as pathogenic.

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