Total submissions: 4
| 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 | 2017-05-25 | criteria provided, single submitter | clinical testing | The G256E pathogenic variant in the MYH7 gene has been reported previously in a large kindred of individuals with HCM of whom 39 individuals harbored G256E (Fananapazir et al., 1993; Fananapazir et al., 1994). Fananapazir et al. (1994) reported that disease penetrance in this kindred was approximately 56% in adults and 60% in children with only one instance of sudden death observed. Kaski et al. (2009) identified the G256E variant in a preadolescent child with HCM. G256E has been observed in one other proband referred for HCM testing at GeneDx.The G256E variant is 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. Moreover, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to protein structure/function.In addition, using in vitro motility studies, Cuda et al. (1997) demonstrated that mutant myosins, including G256E, move actin filaments more slowly when compared to control samples. Lastly, the G256E variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). |
| Invitae | RCV000693916 | SCV000822339 | likely pathogenic | Hypertrophic cardiomyopathy | 2018-08-03 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine with glutamic acid at codon 256 of the MYH7 protein (p.Gly256Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with hypertrophic cardiomyopathy (HCM) in a large multigenerational family (PMID: 8281650). In addition it has been reported in several independent individuals with HCM, one of whom also carried a pathogenic variant in the TNNT2 gene (PMID: 20031618, 27532257, 18761664), and in an individual with central core disease (PMID: 8483915). ClinVar contains an entry for this variant (Variation ID: 14099). 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). 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). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| OMIM | RCV000015155 | SCV000035412 | pathogenic | Familial hypertrophic cardiomyopathy 1 | 1993-05-01 | no assertion criteria provided | literature only |