ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2605C>T (p.Arg869Cys)

dbSNP: rs730880750
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute RCV000853471 SCV000996382 likely pathogenic Hypertrophic cardiomyopathy 2017-11-13 criteria provided, single submitter research The MYH7 Arg869Cys variant has been previously reported in several HCM probands (Genedx, Pers. Comm.; Captur G, et al., 2014; Liu X et al., 2014; Fujita T, et al., 2013; Hirota T, et al., 2010; Anan R, et al., 2000), and has been found to segregate in familial cases (Genedx, Pers. Comm.; Anan R et al., 2000). We identified this variant in a HCM proband of European descent who has no family history of HCM or sudden death. The variant is absent from the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), as well as the Genome Aggregation Database (http://gnomad.broadinstitute.org/). In a large HCM population study Walsh et al., identified that MYH7 variants identified in HCM cases were found to cluster between amino acids 181- 937 (2017), this implies that variants in this region are likely to cause a HCM phenotype. Interestingly, different rare variants at this position (Arg869His & Arg869Ser) have also been reported in multiple HCM individuals, suggesting that an amino acid substitution at this site may not be tolerated. Computational tools SIFT, MutationTaster, PolyPhen-2 and PolyPhen-HCM predict this variant to be deleterious. In summary, based on rarity in the general population, presence and segregation in HCM families, in silico tools predicting a deleterious affect and because the variant is located in a well known "hotspot" of MYH7 we classify MYH7 Arg689Cys as a "likely pathogenic" variant.
Invitae RCV000853471 SCV001496999 pathogenic Hypertrophic cardiomyopathy 2023-12-30 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 869 of the MYH7 protein (p.Arg869Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 10862102, 24621997, 24704860, 27247418, 30588760, 32894683). ClinVar contains an entry for this variant (Variation ID: 181196). 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 is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). This variant disrupts the p.Arg869 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17180650, 20359594, 23674513, 24093860, 25078086). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV001798536 SCV002042278 likely pathogenic Cardiomyopathy 2022-09-14 criteria provided, single submitter clinical testing
Ambry Genetics RCV002426779 SCV002741359 likely pathogenic Cardiovascular phenotype 2023-08-29 criteria provided, single submitter clinical testing The p.R869C variant (also known as c.2605C>T), located in coding exon 20 of the MYH7 gene, results from a C to T substitution at nucleotide position 2605. The arginine at codon 869 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration is located in the myosin head domain, which contains a statistically significant clustering of pathogenic missense variants (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;19:192-203; Ambry internal data). This variant has been detected in individuals with hypertrophic cardiomyopathy (HCM) or from HCM cohorts, and has been reported to segregate with disease in a family; however, segregation details were limited (Anan R et al. Hum Mutat, 2000 Jun;15:584; Hirota T et al. J Cardiol, 2010 Jul;56:59-65; Fujita T et al. JACC Heart Fail, 2013 Dec;1:459-66; Captur G et al. Circ Cardiovasc Genet, 2014 Jun;7:241-8; Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309; Mattivi CL et al. Circ Genom Precis Med, 2020 10;13:453-459). This variant has also been seen in HCM cases who had variants in other cardiomyopathy-related genes (Hershkovitz T et al. Am J Med Genet A, 2019 03;179:365-372; Kubo T et al. Circ J. 2011 Jul;75(11):2654-9Lopes LR et al. Eur Heart J. 2021 08;42(32):3063-3073). Another variant affecting this codon (p.R869H, c.2606G>A) has also been reported in association with HCM (Maurizi N et al. JAMA Cardiol, 2018 Jun;3:520-525). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV003335142 SCV004046313 likely pathogenic MYH7-Related Disorders criteria provided, single submitter clinical testing This variant has been previously reported as a heterozygous change in multiple patients with hypertrophic cardiomyopathy (HCM; PMID: 30588760, 10862102, 24621997, 30847666, 32894683). It is absent from the gnomAD population database and thus presumed to be rare. The c.2605C>T (p.Arg869Cys) variant is found in the head region of the MYH7 protein (residues 181-937) where missense variants are statistically more likely to be associated with HCM (PMID:27532257, 29300372). Different missense variants involving the same amino acid position have been previously reported in individuals with HCM in the Human Gene Mutation Database (HGMD; PMID: 32596782). The MYH7 gene is constrained against missense variation (Z-score= 3.93), and missense variants are an established mechanism of disease (PMID: 29300372). Based on the available evidence, the c.2605C>T (p.Arg869Cys) variant is classified as Likely Pathogenic.
Color Diagnostics, LLC DBA Color Health RCV001798536 SCV004356911 likely pathogenic Cardiomyopathy 2023-10-16 criteria provided, single submitter clinical testing This missense variant replaces arginine with cysteine at codon 869 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). This variant is found within a highly conserved region of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 10862102, 21799269, 24704860, 30588760, 33495597, 34263907; SCV000996382.2) as well as in individuals with left ventricular hypertrophy (PMID: 24621997). One of these individuals also carried a pathogenic variant in the MYBPC3 gene (PMID: 21799269). A different variant occurring at the same codon, p.Arg869His, is a pathogenic mutation (Clinvar variation ID: 177667), indicating that arginine at this position is important for MYH7 protein function. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

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