ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.5342G>A (p.Arg1781His)

gnomAD frequency: 0.00002  dbSNP: rs397516246
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel RCV000234735 SCV001976480 uncertain significance Hypertrophic cardiomyopathy 2021-08-25 reviewed by expert panel curation The c.5342G>A (p.Arg1781His) variant in MYH7 has been identified in at least 12 individuals with HCM (PS4_Moderate; Lopes 2015 PMID: 25351510; Walsh 2017 PMID: 27532257; GeneDx pers comm; Invitae pers comm; LMM pers comm; OMGL pers comm). This variant was identified in 0.00116% (FAF 95% CI; 2/30616) of South Asian chromosomes by gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to a lack of evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate, PM2, PP3.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV001550459 SCV000059611 uncertain significance not provided 2023-08-07 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Invitae RCV000234735 SCV000284285 pathogenic Hypertrophic cardiomyopathy 2023-10-28 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1781 of the MYH7 protein (p.Arg1781His). This variant is present in population databases (rs397516246, gnomAD 0.003%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 17125710, 27532257; Invitae). ClinVar contains an entry for this variant (Variation ID: 43064). 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%. For these reasons, this variant has been classified as Pathogenic.
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV000234735 SCV000492983 uncertain significance Hypertrophic cardiomyopathy 2014-01-21 criteria provided, single submitter clinical testing
GeneDx RCV001550459 SCV001770786 uncertain significance not provided 2022-01-19 criteria provided, single submitter clinical testing Variant reported in multiple unrelated individuals with HCM in the published literature or referred for genetic testing at GeneDx; however, few clinical details were provided and some individuals harbor additional cardiogenetic variants (Laredo et al., 2006; Kaski et al., 2009; Lopes et al., 2015; Homburger et al., 2016; Alamo et al., 2017; Mademont-Soler et al., 2017; Walsh et al., 2017); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar (ClinVar Variant ID# 43064; ClinVar); This variant is associated with the following publications: (PMID: 27532257, 17125710, 20031618, 25351510, 28606303, 28771489, 27247418, 29687901, 24111713, 32531501)
Ambry Genetics RCV002345280 SCV002647064 uncertain significance Cardiovascular phenotype 2023-04-03 criteria provided, single submitter clinical testing The p.R1781H variant (also known as c.5342G>A), located in coding exon 35 of the MYH7 gene, results from a G to A substitution at nucleotide position 5342. The arginine at codon 1781 is replaced by histidine, an amino acid with highly similar properties. This variant has been detected in individuals from hypertrophic cardiomyopathy (HCM) cohorts; however, in some instances clinical detail was limited and co-occurring variants were present, and some reports may overlap (Laredo R et al. Rev Esp Cardiol, 2006 Oct;59:1008-18; Lopes LR et al. J. Med. Genet., 2013 Apr;50:228-39; Walsh R et al. Genet. Med., 2017 02;19:192-203; Mademont-Soler I et al. PLoS ONE, 2017 Aug;12:e0181465; Mazzarotto F et al. Genet. Med., 2019 02;21:284-292; Azevedo O et al. Am. Heart J., 2020 Apr;226:114-126). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics RCV002477078 SCV002792575 uncertain significance Hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Congenital myopathy with fiber type disproportion; Dilated cardiomyopathy 1S; MYH7-related skeletal myopathy 2021-09-04 criteria provided, single submitter clinical testing

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