Submissions for variant NM_000257.4(MYH7):c.5344A>G (p.Met1782Val)

dbSNP: rs727504385

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000168424	SCV000219120	pathogenic	Hypertrophic cardiomyopathy	2023-11-25	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1782 of the MYH7 protein (p.Met1782Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 25611685, 26914223, 27247418, 27532257; Invitae). ClinVar contains an entry for this variant (Variation ID: 177892). 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%. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000786171	SCV001792469	uncertain significance	not provided	2020-10-19	criteria provided, single submitter	clinical testing	Reported in ClinVar (ClinVar Variant ID# 177892; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); 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: 26914223, 27247418, 27532257, 25611685, 28606303, 30297972)
Ambry Genetics	RCV002345495	SCV002643277	uncertain significance	Cardiovascular phenotype	2018-02-21	criteria provided, single submitter	clinical testing	The p.M1782V variant (also known as c.5344A>G), located in coding exon 35 of the MYH7 gene, results from an A to G substitution at nucleotide position 5344. The methionine at codon 1782 is replaced by valine, an amino acid with highly similar properties. This alteration has been reported in association with hypertrophic cardiomyopathy; however, clinical information was limited in most cases, and segregation information was not available (Alfares AA et al. Genet. Med., 2015 Nov;17:880-8; Homburger JR et al. Proc. Natl. Acad. Sci. U.S.A., 2016 06;113:6701-6; Murphy SL et al. J Cardiovasc Transl Res, 2016 Apr;9:153-61; Walsh R et al. Genet. Med., 2017 Feb;19:192-203). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154544	SCV000204217	uncertain significance	not specified	2015-11-13	no assertion criteria provided	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786171	SCV000924876	uncertain significance	not provided	2016-09-12	no assertion criteria provided	provider interpretation	p.Met1782Val (c.5344A>G) in the MYH7 gene (NM_000257.3) We have seen this variant in one Caucasian individual with HCM. Given the location, absence from population databases and presence in a small number of affected patients (but without segregation or functional data), we consider this variant a variant of uncertain significance, probably disease causing and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least 3 unrelated cases of hypertrophic cardiomyopathy (HCM) (not including this patient's family). There is weak case data. A 2015 study by Alfares et al assessed 2912 unrelated nonsyndromic HCM probands and 1209 family members referred between 2004 and 2013. Testing of up to 51 genes associated with HCM was conducted. The variant of interest was identified in a single proband and classified as “likely pathogenic,” though segregation information is not available. Per the Invitae report: “This variant has been observed in two unrelated patients with obstructive HCM who had positive family histories (Invitae database).” The variant is not in the head (the head is enriched for pathogenic variation). In addition, the variant is not in any of the regions we found enriched for pathogenic variation when comparing HCM patients to ExAC (Homburger et al 2016). There is no variation at codon 1782 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of 4/12/16). Median coverage at that site is 100.