Submissions for variant NM_000257.4(MYH7):c.2804A>T (p.Glu935Val)

gnomAD frequency: 0.00001  dbSNP: rs730880761

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel	RCV001313026	SCV001842652	uncertain significance	Hypertrophic cardiomyopathy	2021-06-16	reviewed by expert panel	curation	The c.2804A>T (p.Glu935Val) variant in MYH7 has been identified in at least 1 individual with early-onset HCM (<25 yo) who also carried a second MYH7 variant (Rubattu 2016 PMID:27483260; Cecconi 2016 PMID:27600940). Due to the potential overlap in these cohorts and the presence of a second variant, the PS4_Supporting criterion is not met. This variant was also identified in 0.0003% (FAF 95% CI; 2/113768) of non-Finnish European chromosomes in gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org/). 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, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PM2; PM1; PP3
GeneDx	RCV000158577	SCV000208512	uncertain significance	not provided	2024-06-06	criteria provided, single submitter	clinical testing	Reported in at least one Italian patient with early-onset HCM; however, a second cardiogenetic variant was identified in at least one individual (Rubattu et al., 2016; Cecconi et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29687901, 27600940, 27483260, 31589614, 27532257, 29300372, 34542152, 37589201, 36481846, 36515421)
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV004528897	SCV000930212	likely pathogenic	MYH7-related disorder	2019-04-27	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000790958	SCV000930213	likely pathogenic	MYH7-related skeletal myopathy	2019-04-27	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV003320119	SCV000930214	likely pathogenic	Myosin storage myopathy	2019-04-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001187170	SCV001353885	uncertain significance	Cardiomyopathy	2020-10-20	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with valine at codon 935 of the MYH7 protein. Computational prediction suggests that this variant may have 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 been reported in 1 individual affected with hypertrophic cardiomyopathy (PMID: 27483260). This variant has been identified in 2/251492 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001313026	SCV001503501	uncertain significance	Hypertrophic cardiomyopathy	2023-08-20	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 935 of the MYH7 protein (p.Glu935Val). This variant is present in population databases (rs730880761, gnomAD 0.002%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27483260, 27600940). ClinVar contains an entry for this variant (Variation ID: 181207). 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. 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.
Ambry Genetics	RCV002433702	SCV002749785	uncertain significance	Cardiovascular phenotype	2022-02-10	criteria provided, single submitter	clinical testing	The p.E935V variant (also known as c.2804A>T), located in coding exon 21 of the MYH7 gene, results from an A to T substitution at nucleotide position 2804. The glutamic acid at codon 935 is replaced by valine, an amino acid with dissimilar properties, and is located in the myosin head domain. This variant was detected in an individual with hypertrophic cardiomyopathy; however, another MYH7 variant was also reported and clinical details were limited (Rubattu S et al. Int J Mol Sci, 2016 Jul;17:[Epub ahead of print]; Cecconi M et al. Int J Mol Med, 2016 Oct;38:1111-24). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002478478	SCV002778401	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	2021-07-29	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001187170	SCV004833255	uncertain significance	Cardiomyopathy	2023-08-15	criteria provided, single submitter	clinical testing