Submissions for variant NM_000257.4(MYH7):c.1826A>G (p.Tyr609Cys)

dbSNP: rs727504925

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000557354	SCV000206034	likely pathogenic	Hypertrophic cardiomyopathy	2019-03-07	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Labcorp Genetics (formerly Invitae), Labcorp	RCV000557354	SCV000623652	likely pathogenic	Hypertrophic cardiomyopathy	2024-04-25	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 609 of the MYH7 protein (p.Tyr609Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 21750094, 27247418, 31737537). ClinVar contains an entry for this variant (Variation ID: 179525). 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 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.
Ambry Genetics	RCV002408697	SCV002713138	likely pathogenic	Cardiovascular phenotype	2022-06-16	criteria provided, single submitter	clinical testing	The p.Y609C variant (also known as c.1826A>G), located in coding exon 14 of the MYH7 gene, results from an A to G substitution at nucleotide position 1826. The tyrosine at codon 609 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration is located in the myosin head domain, which contains a statistically significant clustering of pathogenic missense variants (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;19:192-203; Ambry internal data). This variant has been reported in several hypertrophic cardiomyopathy (HCM) cases (Waldmüller S et al. Eur J Heart Fail, 2011 Nov;13:1185-92; Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298; Harper AR et al. Nat Genet, 2021 02;53:135-142). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx	RCV004700484	SCV005201579	likely pathogenic	not provided	2023-07-16	criteria provided, single submitter	clinical testing	Reported in individuals with hypertrophic cardiomyopathy (HCM) from large cohort studies, but detailed clinical information and familial segregation information were not provided (Waldmuller et al., 2011; Homburger et al., 2016; Marschall et al., 2019; Harper et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33495597, 31737537, 27247418, 21750094, 27532257, 29300372)