ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2080C>T (p.Arg694Cys)

gnomAD frequency: 0.00001  dbSNP: rs727504240
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000628970 SCV000203858 likely pathogenic Hypertrophic cardiomyopathy 2019-09-19 criteria provided, single submitter clinical testing The p.Arg694Cys variant in MYH7 has been reported in at least 11 individuals with HCM and segregated with disease in 3 affected relatives from 2 families (Andersen 1999 and 2004, Van Driest 2004, Witjas-Paalberends 2013, Alfares 2015, GeneDx pers comm, LMM data). At least 4 individuals carried additional likely disease causing variants in the MYBPC3 gene (Van Driest 2004, GeneDx pers comm). In addition, this variant has been identified in 5/251358 chromosomes by gnomAD (http://gnomad.broadinstitute.org) and reported in ClinVar (Variant ID: 177627). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Of note, this variant lies in the head region of the protein, and missense variants in this region are statistically more likely to be disease-associated (Walsh 2016). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PS4_Moderate, PM1, PM2, PP3, PP1.
GeneDx RCV001723720 SCV000208441 likely pathogenic not provided 2022-07-18 criteria provided, single submitter clinical testing Identified in several individuals with HCM in published literature, though some of these individuals also harbored reportedly pathogenic variants in other HCM-related genes (Andersen et al., 1999; Van Driest et al., 2004; Olivotto et al., 2008; Walsh et al., 2017; Mattivi et al., 2020); Identified independently and in conjunction with additional cardiogenetic variants in individuals referred for cardiomyopathy genetic testing at GeneDx, and it was observed to segregate with cardiomyopathy in at least one family member; 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: 26688388, 21310275, 34542152, 31737537, 32528171, 23197161, 24928957, 18533079, 18761664, 20031602, 25524337, 12566107, 15114369, 15519027, 27532257, 15358028, 25611685, 20819418, 28606303, 27247418, 23674513, 29300372, 32894683, 32369506, 31323898, 10563488)
Ambry Genetics RCV000618360 SCV000740227 likely pathogenic Cardiovascular phenotype 2022-08-19 criteria provided, single submitter clinical testing The p.R694C variant (also known as c.2080C>T), located in coding exon 17 of the MYH7 gene, results from a C to T substitution at nucleotide position 2080. The arginine at codon 694 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 alteration has been reported in multiple individuals with hypertrophic cardiomyopathy (HCM), including some cases with additional cardiac variants detected (Andersen PS et al. Eur. J. Hum. Genet., 2004 Aug;12:673-7; Van Driest SL et al. J. Am. Coll. Cardiol., 2004 Nov;44:1903-10; Walsh R et al. Genet. Med., 2017 02;19:192-203; Ho CY et al. Circulation, 2018 10;138:1387-1398). Another alteration at the same codon, p.R694H c.2081G>A, have been reported in several patients from HCM (Erdmann J et al. Clin Genet. 2003;64(4):339-49; Berge KE and Leren TP. Clin Genet. 2014;86(4):355-60; Lopes LR et al. Heart. 2015;101(4):294-301; GeneDx pers. comm.; Invitae pers. comm.; Ambry internal data).This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV000628970 SCV000749880 pathogenic Hypertrophic cardiomyopathy 2023-10-10 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 694 of the MYH7 protein (p.Arg694Cys). This variant is present in population databases (rs727504240, gnomAD 0.006%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 10563488, 12566107, 15114369, 15519027, 22811549, 23674513, 25611685, 27247418, 27532257, 31737537, 32894683; Invitae). ClinVar contains an entry for this variant (Variation ID: 177627). 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. 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.Arg694 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been observed in individuals with MYH7-related conditions (PMID: 12974739, 20819418), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Broad Institute Rare Disease Group, Broad Institute RCV000663405 SCV000786691 uncertain significance MYH7-related skeletal myopathy criteria provided, single submitter research The heterozygous p.Arg694Cys variant in MYH7 has been identified by our project in one individual with distal myopathy. This variant has been reported in at least 11 individuals with HCM, and was found to segregate with disease in 3 affected relatives across 2 families (Andersen 1999, Van Driest 2004, Witjas-Paalberends 2013, Alfares 2015, pers comm). However, at least 4 of those individuals, including the individual reported by Van Driest, also carried an additional likely disease causing variant in the MYBPC3 gene (Van Driest 2004, pers comm). Additionally, this variant has been reported in ClinVar by two seperate clinical laboratories that both currently classify it as a Variant of Uncertain Significance (LMM pers comm, Variant ID: 177627). Other missense variants at the same residue (Arg694Leu, Arg694His) have been reported in the Human Gene Mutation Database in association with cardiomyopathy, however they are both of uncertain significance (Stenson et al., 2014). This variant has been identified in 0.01% (1/17,248) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs727504240). In summary, the clinical significance of the p.Arg694Cys variant is uncertain.
Color Diagnostics, LLC DBA Color Health RCV003531980 SCV004356930 likely pathogenic Cardiomyopathy 2022-03-04 criteria provided, single submitter clinical testing This missense variant replaces arginine with cysteine at codon 694 of the MYH7 protein. 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). 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 at least 15 unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 10563488, 15519027, 18533079, 23674513, 24793961, 25524337, 27247418, 27532257, 32228044, 32369506), including 5 of them who also carried a pathogenic variant in the MYBPC3 gene (PMID: 15519027, 18533079, 32228044). It has been shown that this variant segregates with disease in 5 affected individuals in a family (PMID: 10563488, 15114369, 19035361). This variant has also been reported in an individual affected with unexplained limb-girdle weakness (PMID: 32528171). This variant has been identified in 5/251358 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare RCV000786922 SCV000925823 likely pathogenic Hypertrophic cardiomyopathy 1 2018-12-12 no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV001723720 SCV001953165 pathogenic not provided no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV001723720 SCV001963370 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV001723720 SCV001969066 pathogenic not provided no assertion criteria provided clinical testing

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