ClinVar Genomic variation as it relates to human health

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1359 of the MYH7 protein (p.Arg1359Cys). This variant is present in population databases (rs45451303, gnomAD 0.01%). This missense change has been observed in individuals with dilated cardiomyopathy, hypertrophic cardiomyopathy, and/or left ventricular noncompaction (PMID: 18506004, 19412328, 20965760, 28790153; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 178082). 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.Arg1359 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been observed in individuals with MYH7-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

Reported in patients with cardiomyopathy in published literature (PMID: 27066506, 19412328, 21551322, 29447731, 36252119, 35050212, 36396199, 20965760); 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: 21551322, 19412328, 18506004, 28790153, 34542152, 31983221, 32894683, 37652022, 36264615, 36243179, 27066506, 29447731, 36252119, 35050212, 36396199, 20965760, 37342443, 32789579)

This variant is interpreted as a Uncertain Significance - Insufficient Evidence, for Cardiomyopathy, dilated 1S (CMD1S), in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product.

MYH7 Arg1359Cys variant is present in the Genome Aggregation Database (http://gnomad.broadinstitute.org/) at an allele frequency of 0.000081. This variant has been reported in cases with left ventricular noncompaction (Waning et al., 2018; Chang et al., 2011; Klaassen et al., 2008) and DCM (Hershberger et al. 2008). We have identified this variant in a HCM proband diagnosed late in life with no family history of disease and no other variants to explain her phenotype (Ingles J et al., 2017) and second proband with DCM. In silico tools (SIFT, PolyPhen-2, MutationTaster) are in agreement and supportive of deleterious role. Based on this evidence we classify MYH7 Arg1359Cys as a variant of 'uncertain significance'.

The p.Arg1359Cys variant in MYH7 has been reported in 1 individual with LVNC and 2 individuals with DCM (Klaassen 2008, Hershberger 2008, LMM data). It has also been identified in 2/251432 chromosomes by gnomAD and reported in ClinVar (Variation ID #178082). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PS4_Supporting, PP3.

This missense variant replaces arginine with cysteine at codon 1359 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 two individuals affected with left ventricular noncompaction (PMID: 18506004, 20965760), two individuals affected with dilated cardiomyopathy (PMID: 19412328, 35050212), and one individual affected with hypertrophic cardiomyopathy (PMID: 28790153). This variant has been identified in 2/251432 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 missense variant replaces arginine with cysteine at codon 1359 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 two individuals affected with left ventricular noncompaction (PMID: 18506004, 20965760), two individuals affected with dilated cardiomyopathy (PMID: 19412328, 35050212), and one individual affected with hypertrophic cardiomyopathy (PMID: 28790153). This variant has been identified in 2/251432 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.

The p.R1359C variant (also known as c.4075C>T), located in coding exon 28 of the MYH7 gene, results from a C to T substitution at nucleotide position 4075. The arginine at codon 1359 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been reported with a variety of cardiac phenotypes, including left ventricular non-compaction (LVNC), dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), and sudden infant death syndrome (SIDS) (Hershberger RE et al. Clin Transl Sci, 2008 May;1:21-6; Klaassen S et al. Circulation, 2008 Jun;117:2893-901; Probst S et al. Circ Cardiovasc Genet, 2011 Aug;4:367-74; Burns C et al. Circ Cardiovasc Genet, 2017 Aug;10:[Epub ahead of print]; Köffer J et al. Int J Legal Med. 2021 Jan;135(1):207-212). 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.