ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.1357C>T (p.Arg453Cys) (rs121913625)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000015145 SCV000212633 pathogenic Familial 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".
Ambry Genetics RCV000618958 SCV000739964 pathogenic Cardiovascular phenotype 2017-07-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Strong segregation with disease (lod >3 = >10 meioses)
Blueprint Genetics RCV000035717 SCV000264079 pathogenic Primary familial hypertrophic cardiomyopathy 2015-03-12 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
ClinGen Inherited 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
GeneDx RCV000158799 SCV000208734 pathogenic not provided 2017-08-23 criteria provided, single submitter clinical testing p.Arg453Cys (CGC>TGC): c.1357 C>T in exon 14 of the MYH7 gene (NM_000257.2). The R453C mutation in the MYH7 gene has been reported several times in association with HCM (Watkins H et al., 1992; Watkins H et al., 1993; Ko Y et al., 1996; Perrot A et al., 2005). Watkins et al. reported that the MYH7 mutation R453C co-segregated with HCM in affected members of two families (Watkins H et al., 1992; Watkins H et al., 1993). The NHLBI Exome Sequencing Project reports R453C was not observed in approximately 6,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. R453C results in a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Furthermore, other mutations at the same residue (R453H, R453L, R453S) and in nearby residues (K450T, K450E, I457T) have been reported in association with HCM, further supporting the functional importance of this residue and this region of the protein. In summary, R453C in the MYH7 gene is interpreted as a disease-causing mutation. The variant is found in HCM panel(s).
Invitae RCV000230258 SCV000284255 pathogenic Hypertrophic cardiomyopathy 2018-11-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 453 of the MYH7 protein (p.Arg453Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (rs121913625, ExAC no frequency). This variant has been reported in the literature in multiple unrelated patients and families affected with hypertrophic cardiomyopathy (PMID: 11133230, 12975413, 17599605, 20031618 23283745, 24093860, 24111713). In addition, in several families, it has been reported to segregate with disease (PMID: 8250038, 1552912, 1739523, 1975599). ClinVar contains an entry for this variant (Variation ID: 14089). Experimental studies have shown that this missense change significantly decreases the maximum rate of ATP turnover with a large increase in the maximal force-generating capacity, and a higher number of cross-bridges in the sarcomere (PMID: 15001446, 17351073, 23798412, 24344137). Overall, these studies suggest that this variant causes a hypercontractile state in the heart muscle. A different missense substitution at this codon (p.Arg453His) is reported to be deleterious (PMID: 15858117). This indicates that the arginine residue is important for MYH7 protein function. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare 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.
Laboratory of Genetics and Molecular Cardiology,University of São Paulo RCV000015145 SCV000256122 likely pathogenic Familial hypertrophic cardiomyopathy 1 criteria provided, single submitter clinical testing
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
OMIM RCV000015145 SCV000035402 pathogenic Familial 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).

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