ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.1318G>A (p.Val440Met) (rs397516098)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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 2018-03-13 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 440 of the MYH7 protein (p.Val440Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 15358028). ClinVar contains an entry for this variant (Variation ID: 42835). A computational algorithm designed to assess the pathogenicity of variants in MYH7 with regard to hypertrophic cardiomyopathy predicted this sequence change to be deleterious. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). 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 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.

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