Submissions for variant NM_000257.4(MYH7):c.493A>G (p.Met165Val)

gnomAD frequency: 0.00001  dbSNP: rs730880839

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766401	SCV000208672	uncertain significance	not provided	2017-04-04	criteria provided, single submitter	clinical testing	The Met165Val variant in the MYH7 gene has not been reported as a pathogenic variant or as a benign polymorphism to our knowledge. Met165Val results in a conservative amino acid substitution of one non-polar amino acid for another at a position that is conserved across species. In silico analysis predicts Met165Val is damaging to the protein structure/function. Variants in nearby residues (Tyr162Cys, Tyr162His, Tyr177Ile) have been reported in association with cardiomyopathy, further supporting the functional importance of this region of the protein. Furthermore, Met165Val was not present in the 1000 Genomes database, and the NHLBI ESP Exome Variant Server reports Met165Val was not observed in approximately 6000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Color Diagnostics, LLC DBA Color Health	RCV001191621	SCV001359507	uncertain significance	Cardiomyopathy	2023-09-08	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with valine at codon 165 of the MYH7 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MYH7-related disorders in the literature. This variant has been identified in 3/282874 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Invitae	RCV001369678	SCV001566125	likely pathogenic	Hypertrophic cardiomyopathy	2023-12-31	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 165 of the MYH7 protein (p.Met165Val). This variant is present in population databases (rs730880839, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with MYH7-related conditions. ClinVar contains an entry for this variant (Variation ID: 181307). 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%. This variant disrupts the p.Met165 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Fulgent Genetics, Fulgent Genetics	RCV002498789	SCV002815050	uncertain significance	Hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Congenital myopathy with fiber type disproportion; Dilated cardiomyopathy 1S; MYH7-related skeletal myopathy	2021-08-06	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003895070	SCV004713408	uncertain significance	MYH7-related condition	2023-11-29	criteria provided, single submitter	clinical testing	The MYH7 c.493A>G variant is predicted to result in the amino acid substitution p.Met165Val. This variant has been reported in 4 unaffected individuals from a cardiomyopathy cohort study (Table S6, Park et al. 2022. PubMed ID: 34542152). This variant is reported in 0.0028% of alleles in individuals of Latino descent in gnomAD. An alternate nucleotide change affecting the same amino acid (p.Met165Ile) has been reported in an individual with left ventricular non-compaction and 2 individuals with dilated cardiomyopathy, but was interpreted as uncertain significance (Online Table 1a, van Waning et al. 2018. PubMed ID: 29447731; Table S2, van der Meulen et al. 2022. PubMed ID: 36178741 ). At this time, the clinical significance of the c.493A>G (p.Met165Val) variant is uncertain due to the absence of conclusive functional and genetic evidence.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000223786	SCV000280356	uncertain significance	not specified	2012-08-22	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Met165Val (M165V; c.493 A>G) in the MYH7 gene This variant is completely novel, and has not been previously reported as a disease-causing mutation or as a benign polymorphism. Variation at nearby residues in MYH7 has been associated with cardiomyopathy, supporting the functional importance of this region of the protein: Tyr162Cys, Tyr162His, Thr177Ile (HGMD via GeneDx). This is a conservative amino acid change from a nonpolar methionine to a nonpolar valine. The methionine at codon 165 is absolutely conserved across 32 vertebrate species examined. Some nearby residues are also highly conserved. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “benign” with a score of 0.237. GeneDx reports that “in silico analysis predicts Met165Val is damaging to the protein structure/function.” In total this variant has not been seen in ~7500 individuals from publicly available population datasets, ~4679 of them ethnicity-matched to our Caucasian patient. No variation at this codon is present in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals (as of 1/7/2013). No variation at this codon is present in dbSNP or in 1000 genomes (made up of 1092 individuals of various races, 379 of them with European backgrounds). GeneDx did not report controls.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000766401	SCV001956775	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000766401	SCV001968111	uncertain significance	not provided		no assertion criteria provided	clinical testing