ClinVar Genomic variation as it relates to human health

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

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.

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.

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.

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)