Total submissions: 13
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular Medicine, |
RCV000629015 | SCV000059648 | uncertain significance | Hypertrophic cardiomyopathy | 2021-11-19 | criteria provided, single submitter | clinical testing | proposed classification - variant undergoing re-assessment, contact laboratory |
Labcorp Genetics |
RCV000629015 | SCV000749925 | pathogenic | Hypertrophic cardiomyopathy | 2023-10-23 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 243 of the MYH7 protein (p.Arg243Cys). This variant is present in population databases (rs397516265, gnomAD 0.007%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 21799269, 27247418, 27532257). ClinVar contains an entry for this variant (Variation ID: 43101). 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. This variant disrupts the p.Arg243 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18506004, 20965760, 21551322; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
Color Diagnostics, |
RCV001188097 | SCV001355065 | likely pathogenic | Cardiomyopathy | 2023-11-14 | criteria provided, single submitter | clinical testing | This missense variant replaces arginine with cysteine at codon 243 of the MYH7 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. This variant is found within a highly conserved region of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). Experimental functional studies using human induced pluripotent stem cells have shown that this variant causes impaired cardiomyocyte relaxation and increased multinucleation (PMID: 33705529). This variant has been reported in at least six individuals affected with hypertrophic cardiomyopathy (PMID: 21799269, 27247418, 27532257, 30297972, 32815737, 32830170). This variant has been identified in 1/31404 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. |
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, |
RCV001256698 | SCV001433101 | likely pathogenic | Hypertrophic cardiomyopathy 1 | 2020-05-16 | criteria provided, single submitter | clinical testing | |
Gene |
RCV001569534 | SCV001793639 | likely pathogenic | not provided | 2023-08-12 | criteria provided, single submitter | clinical testing | 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: 20350521, 21799269, 27247418, 27532257, 29121657, 25132132, 32830170, 33705529, 30297972, 35653365, 33487615, 29300372) |
CHEO Genetics Diagnostic Laboratory, |
RCV001188097 | SCV002042702 | likely pathogenic | Cardiomyopathy | 2020-12-14 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV002381295 | SCV002671525 | likely pathogenic | Cardiovascular phenotype | 2024-02-23 | criteria provided, single submitter | clinical testing | The p.R243C variant (also known as c.727C>T), located in coding exon 6 of the MYH7 gene, results from a C to T substitution at nucleotide position 727. The arginine at codon 243 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been reported in association with hypertrophic cardiomyopathy (HCM) (Hirota T et al. J Cardiol, 2010 Jul;56:59-65; Walsh R et al. Genet Med, 2017 Feb;19:192-203; Viswanathan SK et al. PLoS One, 2017 Nov;12:e0187948; Ho CY et al. Circulation, 2018 Oct;138:1387-1398). 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). Another alteration at the same codon, p.R243H (c.728G>A), has been identified in multiple probands with left ventricular noncompaction cardiomyopathy (LVNC), dilated cardiomyopathy, and HCM and has been reported to segregate with disease (Klaassen S et al. Circulation, 2008 Jun;117:2893-901; Chang B et al. Mol. Genet. Metab., 2011 Feb;102:200-6; van Waning JI et al. J. Am. Coll. Cardiol., 2018 Feb;71:711-722; Invitae pers. comm.; OMGL pers. comm.). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
Fulgent Genetics, |
RCV002496549 | SCV002780965 | likely pathogenic | Hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Congenital myopathy with fiber type disproportion; Dilated cardiomyopathy 1S; MYH7-related skeletal myopathy | 2021-07-01 | criteria provided, single submitter | clinical testing | |
Ce |
RCV001569534 | SCV004010268 | likely pathogenic | not provided | 2023-06-01 | criteria provided, single submitter | clinical testing | MYH7: PM1, PM2, PS4:Moderate, PP3 |
All of Us Research Program, |
RCV000629015 | SCV004844794 | likely pathogenic | Hypertrophic cardiomyopathy | 2023-12-18 | criteria provided, single submitter | clinical testing | This missense variant replaces arginine with cysteine at codon 243 of the MYH7 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant is found within a highly conserved region of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). Experimental functional studies using human induced pluripotent stem cells have shown that this variant causes impaired cardiomyocyte relaxation and increased multinucleation (PMID: 33705529). This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 21799269, 27247418, 27532257, 30297972, 32815737, 32830170). This variant has been identified in 1/31404 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. |
Laboratory of Diagnostic Genome Analysis, |
RCV001569534 | SCV001798784 | likely pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Genome Diagnostics Laboratory, |
RCV001569534 | SCV001931548 | likely pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, |
RCV001569534 | SCV001957926 | pathogenic | not provided | no assertion criteria provided | clinical testing |