ClinVar Genomic variation as it relates to human health

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; 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.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

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this mutation in 2 unrelated families (Ingles J, et al., 2005) and have shown this variant to segregate with disease (unpublished data).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".

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: 25351510, 22957257, 16199542, 20359594, 21835320, 21310275, 25524337, 12707239, 26507537, 25935763, 24510615, 27247418, 27532257, 23074333, 9829907, 29300372, 31006259, 30624779, 31447099, 33662488, 33673806, 32880476, 34352619, 34135346, 32894683, 1430197)

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 723 of the MYH7 protein (p.Arg723Cys). This variant is present in population databases (rs121913630, gnomAD 0.003%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy and/or arrhythmogenic right ventricular cardiomyopathy (PMID: 1430197, 9829907, 12117842, 16199542, 25935763, 29709087). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14095). 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%. 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). For these reasons, this variant has been classified as Pathogenic.

proposed classification - variant undergoing re-assessment, contact laboratory

Variant summary: MYH7 c.2167C>T (p.Arg723Cys) results in a non-conservative amino acid change located in the Myosin head, motor domain (IPR001609) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 252214 control chromosomes. c.2167C>T has been widely reported in the literature in individuals affected with Hypertrophic Cardiomyopathy (example, Girolami_2010, Ingles_2005, Jouven_2002, Olivotto_2008, Richard_2003, Watkins_1992). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories and an expert panel (ClinGen Cardiomyopathy Variant Curation Expert Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This missense variant replaces arginine with cysteine at codon 723 of the MYH7 protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. Functional studies using human induced pluripotent stem cells have shown that this variant causes a cellular hypertrophy phenotype in cardiomyocytes (PMID: 35784482). This variant has been reported in over 20 unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 25935763, 29300372, 29710196, 29875424, 31245010, 32481709, 33495596, 33495597, 33673806, 35384713, 36843271), in one individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 29709087), and in one individual affected with dilated cardiomyopathy (PMID: 32880476). This variant has been reported to arise de novo in two individuals affected with hypertrophic cardiomyopathy (PMID: 1430197, 31245010). This variant has also been reported in compound heterozygous state with an MYH7 truncation variant in one individual affected with severe hypertrophic cardiomyopathy (PMID: 20359594). A few family member carriers of this variant have been reported to be unaffected, suggesting a reduced penetrance for this variant (PMID: 9829907, 20359594, 25935763); this variant has also been reported in one healthy older adult (PMID: 34135346). It has been shown that this variant segregates with disease in 3 affected individuals in one family (PMID: 36843271). A different variant affecting the same codon, p.Arg723Gly, is considered to be disease-causing (ClinVar variation ID: 42885), suggesting that arginine at this position is important for MYH7 protein function. This variant has been identified in 3/251214 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

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. 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 variant has been detected in numerous individuals with hypertrophic cardiomyopathy (HCM) 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 with features of HCM (Watkins H et al. J Clin Invest. 1992;90(5):1666-1171). Another alteration at the same codon, p.R723G (c.2167C>G), has also been reported in association with HCM (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.

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 (http://www.ncbi.nlm.nih.gov/clinvar/RCV000035772/#evidence). 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.