ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.1193G>A (p.Gly398Glu)

gnomAD frequency: 0.00002  dbSNP: rs730880158
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel RCV000537983 SCV001976474 uncertain significance Hypertrophic cardiomyopathy 2021-10-01 reviewed by expert panel curation The NM_000257.4(MYH7):c.1193G>A (p.Gly398Glu) variant has been identified in at least 4 individuals with HCM (Olivotto 2008 PMID:18533079; Homburger 2016 PMID:27247428; Invitae pers. comm.). This variant has been identified in 0.00524% (FAF 95% CI; 3/15414) of European chromosomes in genomes only by gnomAD v2.1.1 (https://gnomad.broadinstitute.org), which is too high to apply PM2. However, this represents only a fraction of the total European chromosomes, suggesting low coverage at this locus. Therefore, data from large population studies are insufficient to assess the frequency of this variant. Since the MYH7 specifications state that PS4 is only applicable if the variant is absent or rare in large population studies, the PS4 criterion was not applied (Kelly 2018 PMID:29300372). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be associated with HCM (PM1; Walsh 2017 PMID:27532257). 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): PM1
Invitae RCV000537983 SCV000623636 likely pathogenic Hypertrophic cardiomyopathy 2023-10-18 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 398 of the MYH7 protein (p.Gly398Glu). This variant is present in population databases (rs730880158, gnomAD 0.02%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 18533079, 27247418; Invitae). ClinVar contains an entry for this variant (Variation ID: 180434). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYH7 protein function. 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). 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.
Blueprint Genetics RCV000157354 SCV000207092 uncertain significance Cardiomyopathy 2014-10-28 no assertion criteria provided clinical testing

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