ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.1357C>T (p.Arg453Cys)

gnomAD frequency: 0.00001  dbSNP: rs121913625
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Total submissions: 24
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel RCV000230258 SCV000564414 pathogenic Hypertrophic cardiomyopathy 2016-12-15 reviewed by expert panel curation The c.1357C>T (p.Arg453Cys) variant in MYH7 has been reported in >25 individuals with hypertrophic cardiomyopathy (PS4; PMID:8655135; PMID:10662815; PMID:11133230; PMID:12084606; PMID:12881443; PMID:17599605; PMID:23349452; PMID: 27532257; Partners LMM ClinVar SCV000059368.5; AGCMC Sydney ClinVar SCV000212633.1; SHaRe consortium, PMID: 30297972). This variant has been identified as an unconfirmed de novo occurrence in 3 individuals with hypertrophic cardiomyopathy (PM6_Strong; Partners LMM ClinVar SCV000059368.5). This variant segregated with disease in >10 affected individuals (PP1_Strong: PMID:8655135; PMID:10662815; PMID:11133230; Partners LMM ClinVar SCV000059368.5; AGCMC Sydney ClinVar SCV000212633.1). This variant was absent from large population studies (PM2; http://exac.broadinstitute.org). In vitro functional studies provide some evidence that this variant impacts protein function (PS2; PMID:23798412; PMID:24344137). 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; PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS3; PS4; PM6_Strong; PP1_ Strong; PM1; PM2; PP3
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000230258 SCV000059368 pathogenic Hypertrophic cardiomyopathy 2012-12-06 criteria provided, single submitter clinical testing The p.Arg453Cys variant in MYH7 has been identified in >20 families with HCM or RCM, segregated with disease in >10 affected members of several families, and oc curred de novo in 2 children with HCM (Ko 1996, Forissier 2000, Greber-Platzer 2 001, Ackerman 2002, Garcia-Castro 2003, Nanni 2003, Woo 2003, Van Driest 2004, P errot 2005, LMM unpublished data). It was absent from large population studies ( http://evs.gs.washington.edu/EVS). In summary, this variant meets our criteria t o be classified as pathogenic for HCM in an autosomal dominant manner (http://ww w.partners.org/personalizedmedicine/LMM) based upon segregation studies, de novo occurrences, and absence from controls.
GeneDx RCV000158799 SCV000208734 pathogenic not provided 2022-03-01 criteria provided, single submitter clinical testing Not observed in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect as reduced ATPase activity and enhanced calcium sensitivity result in a hyper-contractile state of the cardiac muscle (Palmer et al., 2004; Debold et al., 2007; Tajsharghi et al., 2008; Sommese et al., 2013; Bloemink et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Classified in ClinVar as a pathogenic variant by the ClinGen Inherited Cardiomyopathy Expert Panel (SCV000564414.4; ClinVar); This variant is associated with the following publications: (PMID: 17351073, 17495353, 15851227, 17599605, 16715312, 18175163, 12707239, 29029073, 1552912, 23283745, 12881443, 15358028, 23349452, 12951062, 15856146, 18365899, 15001446, 23798412, 10662815, 11133230, 27247418, 21310275, 27373729, 27532257, 9541100, 1739523, 24111713, 29300372, 8655135, 12975413, 29907873, 31513939, 32013205, 32283115, 24344137, 31006259, 33673806, 33586461)
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute RCV000015145 SCV000212633 pathogenic Hypertrophic cardiomyopathy 1 criteria provided, single submitter research This MYH7 Arg453Cys mutation is well described in the literature. The mutation has been identified in multiple unrelated individuals and families with HCM (see references). This mutation is not a founder mutation but rather, occurs in a well known hotspot region of the MYH7 gene and has an independent origin is each family (Watkins H, et al., 1993). Additionally, a different mutation affecting the same protein position (Arg453Ser) has been identified to also cause HCM (Frazier A, et al., 2008). Interestingly, this MYH7 Arg453Cys mutation has been identified as the cause of disease in the first HCM family described by Teare in 1958 (Watkins H, et al., 1992). This mutation is inherited as an autosomal trait with high penetrance, has been shown to cosegregate with disease, and is associated with unfavourable prognoses in multiple families (Solomon SD, et al., 1990; Watkins H, et al., 1992 & 1993; Ko YL, et al., 1996; Greber-Platzer S, et al., 2001). We have identified this mutation in one HCM family from our cohort. Based on the available literature, segregation analysis, and absence in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), we classify this variant as "pathogenic".
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000015145 SCV000256122 likely pathogenic Hypertrophic cardiomyopathy 1 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000035717 SCV000264079 pathogenic Primary familial hypertrophic cardiomyopathy 2015-03-12 criteria provided, single submitter clinical testing
Invitae RCV000230258 SCV000284255 pathogenic Hypertrophic cardiomyopathy 2023-12-13 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 453 of the MYH7 protein (p.Arg453Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 1552912, 1739523, 1975599, 8250038, 11133230, 12975413, 17599605, 20031618, 23283745, 24093860, 24111713). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14089). 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%. Experimental studies have shown that this missense change affects MYH7 function (PMID: 15001446, 17351073, 23798412, 24344137). This variant disrupts the p.Arg453 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15858117). 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.
Ambry Genetics RCV000618958 SCV000739964 pathogenic Cardiovascular phenotype 2021-10-25 criteria provided, single submitter clinical testing The p.R453C pathogenic mutation (also known as c.1357C>T), located in coding exon 12 of the MYH7 gene, results from a C to T substitution at nucleotide position 1357. The arginine at codon 453 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 unrelated individuals with hypertrophic cardiomyopathy (HCM) (Ackerman MJ et al. J Am Coll Cardiol. 2002;39(12): 2042-8; García-Castro M et al. Clin Chem. 2003;49(8):1279-85; Nanni L et al. Biochem Biophys Res Commun. 2003;309(2):391-8; Woo A et al. Heart. 2003;89(10):1179-85; Walsh R et al. Genet. Med., 2017 Feb;19:192-203), has been reported to segregate with disease in families (Watkins H et al. N Engl J Med. 1992;326(17):1108-14; Watkins H et al. Am J Hum Genet. 1993;53(6):1180-5; Ko YL et al. Hum Genet. 1996;97(5):585-90; Forissier JF et al. J Med Genet. 2000;37(2):132-4; Greber-Platzer S et al. J Mol Cell Cardiol. 2001;33(1):141-8), and has been reported as occurring de novo in an individual with HCM with restrictive features (Franaszczyk M et al. J Clin Med. 2020 Jan;9(2)). In addition, studies of mouse models harboring this alteration recapitulated HCM phenotype (Palmer BM et al. Am J Physiol Heart Circ Physiol. 2004;287(1):H91-9. Debold EP et al. Am J Physiol Heart Circ Physiol. 2007;293(1):H284-91). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute RCV000035717 SCV000740380 pathogenic Primary familial hypertrophic cardiomyopathy 2017-07-21 criteria provided, single submitter clinical testing
Center for Human Genetics, University of Leuven RCV000230258 SCV000886782 pathogenic Hypertrophic cardiomyopathy 2018-10-31 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV001170514 SCV001333097 pathogenic Cardiomyopathy 2019-07-05 criteria provided, single submitter clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000230258 SCV001449020 pathogenic Hypertrophic cardiomyopathy 2016-02-10 criteria provided, single submitter clinical testing
Loeys Lab, Universiteit Antwerpen RCV001375645 SCV001572573 pathogenic Primary dilated cardiomyopathy 2021-02-26 criteria provided, single submitter clinical testing This sequence change results in a missense variant in the MYH7 gene (p.(Arg453Cys)). (PP2; based on GnomAd constraint matrix). This variant is absent from population databases such as GnomAD (PM2) . This variant has been described in literature in several unrelated individuals. Was found de novo in two children with HCM and showed coseggregation in >20 families (>10 individuals).(PMID:8655135; PMID:10662815; PMID: 11133230; PMID:12084606; PMID:12881443; PMID:12951062; PMID:12975413; PMID:15358028) (PP1; PS2). Functional data of homozygous and hetrozygous mice show that the variant significantly decreases the maximum rate if ATP turnover, resulting in a large increase in the maximal force-generating capacity (PMID: 17351073; PMID:15001446). Similar findings were present in a constructed human MYH7 protein (PMID: 23798412 )(PS3). The variant affects a highly conserved amino acid and another variant that disrupt this amino acid has been reported as pathogenic p.Arg453His (PM5). The variant is located in a region of the MYH7 known as a mutational-hotspot (PM1). Prediction programs all classify this variant as pathogenic (AlignGVGD: C65, pathogenic; Polyphen-2 HumDiv: probably damaging; Polyphen-2 HumVar: probably damaging;; SIFT:deleterious; MutationTaster: disease causing). (PP3). We identified this variant in a patients with familial DCM. In conclusion this variant was classified as pathogenic according to ACMG-guidelines (PS2,PS3, PM1, PM2,PM5,PP1,PP3).
Revvity Omics, Revvity RCV000158799 SCV002017671 pathogenic not provided 2022-08-16 criteria provided, single submitter clinical testing
AiLife Diagnostics, AiLife Diagnostics RCV000158799 SCV002502849 pathogenic not provided 2021-05-28 criteria provided, single submitter clinical testing
Clinical Center for Gene Diagnosis and Therapy, Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University RCV000035717 SCV003932410 pathogenic Primary familial hypertrophic cardiomyopathy 2023-06-01 criteria provided, single submitter clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München RCV000015145 SCV004045796 pathogenic Hypertrophic cardiomyopathy 1 2023-06-27 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV004532356 SCV004719132 pathogenic MYH7-related disorder 2023-11-17 criteria provided, single submitter clinical testing The MYH7 c.1357C>T variant is predicted to result in the amino acid substitution p.Arg453Cys. This variant was reported in more than twenty unrelated individuals with hypertrophic cardiomyopathy (Watkins et al. 1992. PubMed ID: 1552912; Tables S1A and S1B, Walsh et al. 2017. PubMed ID: 27532257; Franaszczyk et al. 2020. PubMed ID: 32013205). Functional studies support the pathogenicity of this variant (Debold et al. 2007. PubMed ID: 17351073; Sommese et al. 2013. PubMed ID: 23798412). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic by ClinGen Cardiomyopathy Variant Curation Expert Panel (www.ncbi.nlm.nih.gov/clinvar/variation/14089/). This variant is interpreted as pathogenic.
OMIM RCV000015145 SCV000035402 pathogenic Hypertrophic cardiomyopathy 1 1996-05-01 no assertion criteria provided literature only
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000158799 SCV000280298 pathogenic not provided 2012-01-31 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Arg453Cys (c.1357 C>T) in MYH7 (NM_000257.2) Given the strong case data, segregation data, and mouse model, we consider this variant very likely disease causing. The variant has been seen in over 15 unrelated cases of HCM with strong segregation data. Watkins et al (1992) reported p.Arg453Cys in two families with HCM with a Lod score of 4.4 in one family and a Lod score of 3.9 in the other. Unfortunately details on the number of affected individuals with the variant in each family was not reported. The same authors then reported a third family with HCM and this variant (Watkins et al 1993). In that paper they demonstrated that the variant occurred on three distinct haplotypes in these three families. Ko et al (1996) reported a Chinese kindred with 8 individuals with HCM and p.Arg453Cys. Forissier et al (2000) reported two siblings with HCM and p.Arg453Cys. Interestingly, this was the first reported case of germline mosaicism in HCM. In a cohort of Australian families with HCM, Greber-Platzer et al (2001) reported one family with two affected individuals with p.Arg453Cys. Ackerman et al (2002) reported a child with HCM and p.Arg453Cys. Richard et al (2003) observed p.Arg453Cys in two unrelated individuals with HCM. In a Spanish cohort, Garcia-Castro et al (2003) observed the variant in one case of HCM. Nanni et al (2003) also observed the variant in one individual with HCM. Woo et al (2003) reported two individuals with this variant and HCM (unclear if they are related to each other). Perrot et al (2005) observed the variant in one individual with HCM. Yu et al (2005) observed the variant in one patient with HCM. The variant has been seen with another variant in at least one case (van Driest et al 2004). The patient also carried p.Gln191del in TNNT2. There are multiple additional reports on the variant that I did not review (including, but not limited to Kubo et al 2007, Solomon et al 1993, Bos et al 2014, Kassem et al 2013). We have seen the variant in one other patient with HCM in our center. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. The arginine at codon 453 is conserved across species, as are neighboring variants. This is a non-conservative amino acid change. There are other variants at this codon: p.Arg453Leu, which we consider a variant of uncertain significance; p.Arg453His, which we consider likely disease causing; p.Arg453Ser, which we have not reviewed. Variants at nearby codons have been reported in association with cardiomyopathy (p.Lys450Glu, p.Lys450Thr). The Seidman group has developed a mouse model with p.Arg453Cys that recapitulates an HCM phenotype (Palmer et al 2004, Debold et al 2007). Some authors have suggested that this variant is associated with a particularly severe phenotype. However, many such assertions made in early studies of HCM genetics were later called in to question when milder cases with such "severe" variants were reported and vice versa (ex. van Driest et al 2002). It is certainly possible that this variant causes a more severe phenotype, however further studies are needed to assess that. In addition, even with such a correlation, there may still be some variability among patients with this variant. In total the variant has not been seen in ~7002 published controls and publicly available population datasets. There is no variation at codon 453 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of July 15th, 2014). The variant was not observed in published controls: 100 (Richard et al 2003), 100 (Garcia-Castro et al 2003), 100 (Nanni et al 2003), 106 (Woo et al 2003), 96 (Perrot et al 2005). The early publications this variant did not report control data. There may be additional control data in the papers we did not review (see references for some of these above).
Clinical Genetics, Academic Medical Center RCV000158799 SCV001923921 pathogenic not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000158799 SCV001930987 pathogenic not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000158799 SCV001954721 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000158799 SCV001968729 pathogenic not provided no assertion criteria provided clinical testing

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