Submissions for variant NM_000257.4(MYH7):c.1318G>A (p.Val440Met)

dbSNP: rs397516098

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel	RCV000697579	SCV001976459	likely pathogenic	Hypertrophic cardiomyopathy	2020-08-12	reviewed by expert panel	curation	The c.1318G>A (p.Val440Met) variant in MYH7 has been reported in at least 3 individuals with HCM (PS4_Supporting; Van Driest 2004 PMID:15358028; Bos 2014 PMID:24793961; Walsh 2017 PMID:27532257; LMM pers comm.; OMGL pers comm.) and 1 individual with RCM (Invitae pers comm.). This variant segregated with HCM in 3 affected relatives from 3 families (PP1; LMM pers comm.; OMGL pers comm.). This variant was absent from large population studies (PM2; http://gnomad.broadinstitute.org, v2.1.1). 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 disease-associated (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. ACMG/AMP Criteria applied: PS4_Supporting; PP1; PM2; PM1; PP3.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000697579	SCV000059364	likely pathogenic	Hypertrophic cardiomyopathy	2017-11-06	criteria provided, single submitter	clinical testing	The p.Val440Met variant in MYH7 has been reported in 5 individuals with HCM (Van Driest 2004; Walsh 2016) and segregated with disease in 2 affected relatives fr om 2 families. This variant was absent from large population studies. This varia nt was predicted to be pathogenic using a computational tool clinically validate d by our laboratory. This tool's pathogenic prediction is estimated to be correc t 94% of the time (Jordan 2011). This variant lies in the head region of the pro tein. Missense variants in this region have been reported and statistically indi cated to be more likely to cause disease (Walsh 2016). In summary, although addi tional studies are required to fully establish its clinical significance, the p. Val440Met variant is likely pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000035713	SCV000747986	likely pathogenic	Primary familial hypertrophic cardiomyopathy	2016-12-22	criteria provided, single submitter	clinical testing
Invitae	RCV000697579	SCV000826199	uncertain significance	Hypertrophic cardiomyopathy	2023-11-13	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 440 of the MYH7 protein (p.Val440Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 15358028, 27532257, 33673806). ClinVar contains an entry for this variant (Variation ID: 42835). 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 with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.