ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2167C>T (p.Arg723Cys) (rs121913630)

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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, RCV000462477 SCV000564425 pathogenic Hypertrophic cardiomyopathy 2016-12-15 reviewed by expert panel curation The c.2167C>T (p.Arg723Cys) variant in MYH7 has been reported in >20 individuals with hypertrophic cardiomyopathy (PS4; PMID:1430197; PMID:27532257; PMID:9829907; PMID:16199542; PMID:20359594; PMID:12707239; Partners LMM ClinVar SCV000059423.5; AGCMC Sydney ClinVar SCV000212630.1). Five of these probands carried additional variants in sarcomere genes (BP2; PMID:20359594; PMID:12707239; Partners LMM ClinVar SCV000059423.5). This variant has been identified as a de novo occurrence in 1 proband with hypertrophic cardiomyopathy (PM6; PMID:1430197). This variant segregated with disease in 7 affected individuals (PP1_Strong; PMID:9829907; Partners LMM ClinVar SCV000059423.5; AGCMC Sydney ClinVar SCV000212630.1). This variant was identified in 2/66738 European chromosomes (PM2; 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.2167C>G p.Arg723Gly - ClinVar Variation ID 42885). In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. The benign evidence code BP2 was not considered to be in conflict with this conclusion given that presence of a second variant can be seen in individuals with cardiomyopathy and may contribute to the severity of disease. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PP1_ Strong; PM1; PM2; PM5; PM6; PP3; BP2
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000462477 SCV000059423 pathogenic Hypertrophic cardiomyopathy 2016-02-12 criteria provided, single submitter clinical testing The p.Arg723Cys variant in MYH7 has been reported in at least 14 individuals wit h HCM, segregated with disease in 7 affected relatives from 3 families, and was reported to have occurred de novo in 1 affected individual with confirmed parent al identities (Watkins 1992, Tesson 1998, Richard 2003, Ingles 2005, Girolami 20 10, Olivotto 2011, LMM data). Moreover, another variant at this position (p.Arg7 23Gly) is pathogenic based on extensive segregation with disease. Of note, the p .Arg723Cys variant was identified in multiple unaffected relatives at older ages and is likely associated with reduced penetrance and a variable disease course (Tesson 1998, Richard 2003, Girolami 2010, LMM data). This variant has been repo rted by other clinical laboratories in ClinVar and was also identified in 2/1114 68 European chromosomes and 1/30782 South Asian chromosomes by the Genome Aggreg ation Database (gnomAD,; dbSNP rs121913630). In summary, this variant meets criteria to be classified as pathogenic for HCM in an autosomal dominant manner based upon presence in multiple affected individual s, segregation studies, de novo occurrence, and low allele frequency in the gene ral population. ACMG/AMP Criteria applied (Richards 2015): PS4, PM2, PS2, PP1_St rong.
GeneDx RCV000158516 SCV000208451 pathogenic not provided 2017-08-14 criteria provided, single submitter clinical testing The R723C pathogenic variant in the MYH7 gene has been reported multiple times in association with HCM (Watkins et al., 1992; Tesson et al., 1998; Richard et al., 2003; Ingles et al., 2005; Girolami et al., 2010; Kapplinger et al., 2014). R723C was first reported by Watkins et al. (1992) in one individual with HCM, and Tesson et al. (1998) subsequently reported R723C in 11 members of a large family with a mild form of HCM. Collectively, R723C was absent from more than 380 alleles of unrelated control subjects (Watkins et al., 1992; Tesson et al., 1998). Furthermore, the R723C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; Exome Variant Server). The R723C variant 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 residue where only amino acids with similar properties to arginine (R) are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, missense variants affecting the same residue (R723G, R723H) and nearby residues (R719P, R719Q, R719W, R721K, A728V, A729P) have been reported in the Human Gene Mutation Database in association with HCM (Stenson et al., 2014).
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000015151 SCV000212630 pathogenic Familial hypertrophic cardiomyopathy 1 criteria provided, single submitter research This MYH7 Arg723Cys variant has previously been identified in a small number of unrelated cases with HCM (see references). The variant was first reported as a de novo mutation (Watkins H, et al., 1992). Segregation analysis has shown this variant to segregate with disease with incomplete penetrance (Tesson F, et al., 1998; Richard P, et al., 2003; Girolami F, et al., 2010). Interestingly, Tesson F (1998) described monozygotic twins who carry this mutation where only one twin had left ventricular hypertrophy. We identified this mutation in 2 unrelated families (Ingles J, et al., 2005) and have shown this variant to segregate with disease (unpublished data). Based on existing reports and our data, we classify this variant as "pathogenic".
Ambry Genetics RCV000253053 SCV000318794 pathogenic Cardiovascular phenotype 2019-07-02 criteria provided, single submitter clinical testing The p.R723C pathogenic mutation (also known as c.2167C>T) is located in coding exon 18 in the MYH7 gene. This variant results from a C to T substitution at nucleotide position 2167. The arginine at codon 723 is replaced by cysteine, an amino acid with highly dissimilar properties. Located in the head domain of the MYH7 protein, this alteration has been detected in numerous individuals with hypertrophic cardiomyopathy and has been reported to segregate with disease in several families (Tesson F et al 1998. Hum Mutat. 1998;12(6):385-392; Richard P et al. Circulation. 2003;107(17):2227-2232; Girolami F et al. J Am Coll Cardiol. 2010;55(4):1444-53; Walsh R et al. Genet. Med., 2017 02;19:192-203; Kelly MA et al. Genet. Med., 2018 03;20:351-359). In addition, this variant was described as de novo in a patient demonstrating typical clinical features of hypertrophic cardiomyopathy (HCM), but other associated HCM genes were not analyzed (Watkins H et al. J Clin Invest. 1992;90(5):1666-1171). A disease-causing mutation (p.R723G) has been described in the same codon (Yang JH et al. Chin Med J (Engl). 2006; 119(21):1785-9). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000462477 SCV000546190 pathogenic Hypertrophic cardiomyopathy 2019-12-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 723 of the MYH7 protein (p.Arg723Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs121913630, ExAC 0.006%). This variant has been reported to segregate with hypertrophic cardiomyopathy in families (PMID: 9829907, 25935763) and has been observed in several unrelated individuals with hypertrophic cardiomyopathy (PMID: 16199542, 12117842). It has also been shown to have arisen de novo, with confirmed paternity, in an affected individual (PMID: 1430197). ClinVar contains an entry for this variant (Variation ID: 14095). A computational algorithm designed to assess the pathogenicity of variants in MYH7 with regard to hypertrophic cardiomyopathy predicted this sequence change to be deleterious. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). A different missense substitution at this codon (p.Arg723Gly) has been determined to be pathogenic (PMID: 11113006, 17097032, 19651039, 20819418, 23318932). This suggests that the arginine residue is critical for MYH7 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000158516 SCV001249810 pathogenic not provided 2019-03-01 criteria provided, single submitter clinical testing
Color RCV001186219 SCV001352585 pathogenic Cardiomyopathy 2020-02-24 criteria provided, single submitter clinical testing
OMIM RCV000015151 SCV000035408 pathogenic Familial hypertrophic cardiomyopathy 1 1992-11-01 no assertion criteria provided literature only
Blueprint Genetics RCV000035772 SCV000188798 likely pathogenic Primary familial hypertrophic cardiomyopathy 2013-12-31 no assertion criteria provided clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000158516 SCV000280314 pathogenic not provided 2012-01-16 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.Arg723Cys (c.2167C>T) in the MYH7 gene. This variant has been seen in at least 6 unrelated families with HCM (not including in our cohort), with strong segregation data in one family. Watkins et al (1992) described the variant in a proband with HCM. Tesson et al (1998) reported this variant with HCM. The variant segregated with HCM in one family; the variant was found in 11 members of a family, 6 of those individuals had HCM. This family had no incidence of early or sudden cardiac death. Richard et al (2003) reported the variant in a patient with HCM who also carried p.Val39Met in MYH7. Two individuals with just p.Arg723Cys had HCM, while individuals with both variants had more severe hypertrophy (on average) (likely the same case as reported in Charron et al 1997). Ingles et al (2005) reported the variant in a patient with HCM from their Australian cohort. Girolami et al (2010) reported a patient with HCM who carried p.Arg723Cys in trans with p.Glu1455Ter as well as p.Glu165Asp in MYBPC3 (same patient reported in Olivotto et al 2011). Maron et al (2012) include an individual with this variant in a paper on myocardial crypts in HCM. That patient is listed as one who does not have a diagnosis of HCM yet but is predisposed and has a family history. No information is provided about family members with HCM who have the variant. LMM submitted their classification of the variant (pathogenic) to ClinVar with a total of 9 families, citing 5 in the literature, which suggests they may have seen the variant in 4 additional families ( Additionally other variants in the same codon (p.Arg723His, p.Arg723Gly) as well as neighboring codons (p.Arg721Lys) have been reported in association with HCM in published literature. Arginine is highly conserved at this position across species. The variant has not been seen in a total of ~6740 publicly available general population samples and published controls. There is no variation at codon 723 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6300 Caucasian and African American individuals (as of 9 December 2013). This variant was not observed in 440 published controls: 90 (Watkins et al 1992), 100 (Tesson et al 1998), 100 (Richard et al 2003), 150 (Ingles et al 2005). The variant is listed in dbSNP (rs121913630), however the submitted data is from LMM and OMIM and thus relates to its presence in affected individuals.

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