ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.1208G>A (p.Arg403Gln) (rs121913624)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Inherited Cardiomyopathy Variant Curation Expert Panel, RCV000199447 SCV000564413 pathogenic Hypertrophic cardiomyopathy 2016-12-15 reviewed by expert panel curation The c.1208G>A (p.Arg403Gln) variant in MYH7 has been reported in >30 individuals with hypertrophic cardiomyopathy and segregated with disease in >30 affected family members (PS4 and PP1_Strong; PMID:1638703; PMID:1975517; PMID:7789380; PMID:12975413; PMID:24268868; PMID:10725281; PMID:20800588; PMID:12707239; PMID:27532257; AGCMC Sydney ClinVar SCV000692503.1; Invitae ClinVar SCV000253815.4; Partners LMM ClinVar SCV000059359.5; SHaRe consortium, PMID: 30297972). Mouse model indicates that this variant disrupts the function of MYH7 and leads to a phenotype consistent with HCM (PS3: PMID:8614836). This variant was absent from large population studies (PM2; http://exac.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; PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). A different pathogenic missense variant has been previously identified at this codon which may indicate that this residue is critical to the function of the protein (PM5; c.1207C>T (p.Arg403Trp) - Variation ID 14102). 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; PP1_ Strong; PM1; PM2; PM5; PP3
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000199447 SCV000059359 pathogenic Hypertrophic cardiomyopathy 2014-12-22 criteria provided, single submitter clinical testing The p.Arg403Gln variant in MYH7 is a well-established, common HCM variant that h as been detected in a large number of individuals with HCM and is absent from la rge population studies. Published evidence sufficient to establish a pathogenic role includes presence in multiple families and segregation with disease in more than 10 affected relatives (Geisterfer-Lowrance 1990, Epstein 1992, Marian 1995 , Richard 2003, Millat 2010). Additional studies have been published but are not included here. Our laboratory has identified this variant in 14 families with H CM. The pathogenicity of this variant is further supported by functional studies using animal models (Georgakopoulos 1999, Tyska 2000, Yamashita 2000, Lowey 201 3) and in vitro analyses, which demonstrate an impact on cardiomyocyte function (Di Domenico 2012, Abraham 2013, Witjas-Paalberends 2014). In summary, this vari ant meets our criteria to be classified as pathogenic for HCM in an autosomal do minant manner (http://www.partners.org/personalizedmedicine/LMM).
GeneDx RCV000158788 SCV000208723 pathogenic not provided 2018-08-28 criteria provided, single submitter clinical testing The R403Q pathogenic variant in the MYH7 gene has been reported multiple times in association with HCM. Patients with this variant may have a more severe phenotype, with early age of onset and a higher rate of premature death (Geisterfer-Lowrance et al., 1990; Epstein et al., 1992; Watkins et al., 1994; Van Driest et al., 2004; Kaski et al., 2009). Geisterfer-Lowrance et al. (1990) found that this variant affects a highly conserved amino acid residue and segregated with HCM in affected members of a large family. Van Driest et al. (2004) and Kaski et al. (2009) reported R403Q in a three month-old infant and an adolescent child (<13 years old) with HCM, respectively. In addition, R403Q has been identified independently in multiple individuals referred for HCM genetic testing at GeneDx, and was observed de novo (without confirmed parentage) in two unrelated probands. Other missense variants in the same amino acid residue (R403W, R403L) have been reported in association with cardiomyopathy (Stenson et al., 2014), further supporting the functional importance of this residue. Expression of R403Q in a transgenic mouse model and subsequent functional studies of mutant myosin heavy chain confirmed the pathogenicity of this variant and suggested that this variant may perturb normal kinetic and mechanic assembly and function of cardiac myosin with a gain-of-function effect (Tyska et al., 2000; Yamashita et al., 2000; Debold et al., 2007). Finally, R403Q is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Invitae RCV000199447 SCV000253815 pathogenic Hypertrophic cardiomyopathy 2019-07-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 403 of the MYH7 protein (p.Arg403Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature strongly segregating with hypertrophic cardiomyopathy (HCM) in several large families (PMID: 12975413, 1638703, 1975517, 23751935) and has also been observed in many other unrelated individuals with HCM (PMID: 10725281). ClinVar contains an entry for this variant (Variation ID: 14087). Experimental studies have shown that this variant disrupts protein function in vitro (PMID: 10882745, 9172070, 9826622, 11227787, 17987111, 18565996), and causes hypertrophic cardiomyopathy in both transgenic mouse and rabbit models (PMID: 8614836, 10606622). In summary, this variant is absent from control individuals, segregates with the phenotype in multiples families, and has been confirmed to have a deleterious effect. For these reasons, this variant has been classified as Pathogenic.
Phosphorus, Inc. RCV000015143 SCV000679780 pathogenic Familial hypertrophic cardiomyopathy 1 2017-08-01 criteria provided, single submitter clinical testing
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000015143 SCV000692503 pathogenic Familial hypertrophic cardiomyopathy 1 2017-03-13 criteria provided, single submitter research The MYH7 Arg403Gln variant has been reported in numerous HCM cases (see literature). This variant is known to have high penetrance and has been described to segregate with disease in multiple large families (Geisterfer-Lowrance AA, et al., 1990; Epstein ND, et al., 1992; Marian AJ, et al.,1995; Richard P, et al., 2003; Woo A, et al., 2003; Millat G, et al., 2010). Many functional studies have been carried out which strongly support the pathogenicity of the variant and its affect on the function of cardiomyocytes (see literature). The variant is absent from the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/) and 1000 genomes project (http://www.1000genomes.org/). We identified this variant in an HCM proband, and 1 other affected family member. In silico tools SIFT, PolyPhen-2 and MutationTaster are all supportive of a deleterious role. Furthermore another pathogenic variant has been reported at the same amino acid position (Arg403Trp), suggesting that an amino acid substitution at this residue is not tolerant to change. In summary, based on multiple reported cases, strong segregation data in literature, functional data supportive of pathogenicity and an additional pathogenic variant at the same residue, we classify MYH7 Arg403Gln as a "pathogenic" variant.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000035708 SCV000747991 pathogenic Primary familial hypertrophic cardiomyopathy 2017-06-16 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000158788 SCV000885784 pathogenic not provided 2017-06-20 criteria provided, single submitter clinical testing The p.Arg403Gln variant (rs121913624) is the first, and one of the most well-studied, pathogenic variants to be associated with familial hypertrophic cardiomyopathy (FHC). Segregation analysis of a large French-Canadian kinship first described in Pare et al (1961) revealed the presence of the p.Arg403Gln variant in all affected family members available for testing (Geisterfer-Lowrance 1990). Following discovery in the index family, the p.Arg403Gln variant was subsequently shown to co-segregate with FHC in three additional families (Epstein 1992 and Marian 1994). A mouse model of hypertrophic cardiomyopathy published in 1996 (Geisterfer-Lowrance et al) was generated by introducing the p.Arg403Gln variant into the murine alpha MHC locus. Mice homozygous for this variant died 7 days after birth, whereas heterozygous mice displayed cardiac dysfunction similar to human carriers (Geisterfer-Lowrance 1996). This variant was recently shown to be present at a frequency of 0.12 percent in a combined cohort of dilated and hypertrophic cardiomyopathy patients (identified in 15 out of 12,224 chromosomes; Walsh 2017) while being absent from general population databases such as 1000 Genomes, the NHLBI GO Exome Sequencing Project (ESP), and the Genome Aggregation Database (gnomAD) browser. Additionally, an expert panel has concluded that this variant meets requirements for classification as pathogenic (see link to ClinVar below).
Center for Human Genetics,University of Leuven RCV000199447 SCV000886779 pathogenic Hypertrophic cardiomyopathy 2018-10-31 criteria provided, single submitter clinical testing
OMIM RCV000015143 SCV000035400 pathogenic Familial hypertrophic cardiomyopathy 1 2003-01-01 no assertion criteria provided literature only
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000158788 SCV000280295 pathogenic not provided 2013-09-01 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. Based on the data reviewed below we consider this variant very likely disease causing. The variant has been seen in at least 12 unrelated cases of HCM with strong segregation data in multiple large kindreds. This variant was the first variant ever associated with HCM. Gesiterfer-Lowrance et al (1990) reported a large French-Canadian family in which 40 family members were affected and shown to have this variant. The same authors later reported the variant in an additional proband (Watkins et al 1992). Epstein et al (1992) reported a kindred with 10 affected individuals with p.Arg403Gln. Marian et al (1994) reported two additional large kindreds with strong segregation data. Goncalves et al (2000) also reported at least one family with HCM and this variant (article unavailable). Richard et al (2003) reported the variant in one individual with HCM. Mohiddin et al (2003) reported the variant in a patient with HCM. Woo et al (2003) reported a kindred with 7 affected individuals with the variant. Van Driest et al (2004) reported one individual with HCM and this variant. We have seen this variant in two unrelated cases of HCM in our center. A mouse model with p.Arg403Gln recapitulates the HCM phenotype (Gesiterfer-Lowrance et al 1996). In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. The arginine at codon 403 is conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at this codon (p.Arg403Trp (very likely disease causing), p.Arg403Leu (likely disease causing) and nearby codons (p.Arg404Leu, p.Arg404Met, p.Arg406Met, p.Arg407Val). Lankford et al (1995) reported that p.Arg403Gln lowered the force/stiffness ratio and depressed the velocity of shortening of slow twitch muscle fibers. Moolman et al (1993) noted that there is a CpG doublet at codon 403 which may likely makes it susceptible to mutation. In total the variant has not been seen in 5100 published controls and publicly available population datsets. There is no variation at codon 403 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~5000 Caucasian and African American individuals (as of 1/14/2012). There is also no variation at this codon listed in 1000 genomes (as of 1/14/2012). p.Arg403Gln is not listed in dbSNP (as of 1/14/2012). The variant was not observed in the following published control samples: 100 (RIchard et al 2003. Early papers on this variant did not report control data.

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