Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000693916 | SCV000059654 | pathogenic | Hypertrophic cardiomyopathy | 2014-01-20 | criteria provided, single submitter | clinical testing | proposed classification - variant undergoing re-assessment, contact laboratory |
| Gene |
RCV000158764 | SCV000208699 | pathogenic | not provided | 2020-08-07 | criteria provided, single submitter | clinical testing | Not observed in large population cohorts (Lek et al., 2016); Reported in ClinVar but additional evidence is not available (ClinVar Variant ID #14099; Landrum et al., 2016); Published in vitro functional studies demonstrate reduced muscle motility activity compared to controls (Cuda et al., 1997); 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: 20031618, 9172070, 8281650, 7883988, 7731997, 12473556, 8483915, 21310275, 27532257, 28166811, 31006259) |
| Labcorp Genetics |
RCV000693916 | SCV000822339 | pathogenic | Hypertrophic cardiomyopathy | 2024-05-04 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 256 of the MYH7 protein (p.Gly256Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 8281650, 8483915, 18761664, 20031618, 27532257, 31006259). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14099). 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. |
| Ambry Genetics | RCV002399324 | SCV002673154 | pathogenic | Cardiovascular phenotype | 2022-10-05 | criteria provided, single submitter | clinical testing | The p.G256E pathogenic mutation (also known as c.767G>A), located in coding exon 7 of the MYH7 gene, results from a G to A substitution at nucleotide position 767. The glycine at codon 256 is replaced by glutamic acid, an amino acid with similar 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 alteration was detected in a large family with hypertrophic cardiomyopathy (HCM) and segregation with disease in numerous family members (Fananapazir L et al. Proc. Natl. Acad. Sci. U.S.A., 1993 May;90:3993-7; Fananapazir L et al. Circulation, 1994 Jan;89:22-32). This alteration has also been reported in HCM cohorts; however, clinical details were limited (Lopes LR et al. Heart, 2015 Feb;101:294-301; Walsh R et al. Genet. Med., 2017 02;19:192-203). Functional studies in soleus muscle cells with this alteration demonstrated slower movement of actin filaments compared to wild-type controls (Cuda G et al. J. Muscle Res. Cell. Motil., 1997 Jun;18:275-83). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by BayesDel in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| OMIM | RCV000015155 | SCV000035412 | pathogenic | Hypertrophic cardiomyopathy 1 | 1993-05-01 | no assertion criteria provided | literature only |