Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Agnes Ginges Centre for Molecular Cardiology, |
RCV000172891 | SCV000223882 | uncertain significance | Hypertrophic cardiomyopathy 1 | 2015-02-25 | criteria provided, single submitter | research | This MYH7 Lys860Glu is a novel finding. To our knowledge, no other variant which results in an amino acid substitution at this location has been observed in either controls or HCM cases. This variant is absent in large population databases including the 1000 genomes project (http://www.1000genomes.org/), and the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), suggesting that an amino acid substitution at this site may not be tolerated. We have identified the MYH7 Lys860Glu variant in 1 individual out of >200 index HCM cases who have been genetically screened. Furthermore, this variant is not detected in >160 in-house exomes of unrelated individuals with diverse cardiac phenotypes. Computational tools predict the MYH7 Lys860Glu variant to be "deleterious" (SIFT) and "disease-causing" (MutationTaster). Additionally, a tool specifically designed to predict the effects of missense variants in HCM genes (Jordan DM, et al., 2011), predicts that this variant is causative of the disease. No other informative relatives were identified in this family for segregation analysis. Based on the absence of this variant in the general population, and predictions from a number of in silico models, we suspect this variant to possibly be disease-causing. At this time however, we do not have sufficient evidence to support its role in disease. Thus, we classify this MYH7 Lys860Glu variant as one of "uncertain significance". |
| Labcorp Genetics |
RCV001852103 | SCV002135877 | uncertain significance | Hypertrophic cardiomyopathy | 2024-03-21 | criteria provided, single submitter | clinical testing | This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 860 of the MYH7 protein (p.Lys860Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 28790153, 32894683). ClinVar contains an entry for this variant (Variation ID: 192312). 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%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Ambry Genetics | RCV002453603 | SCV002739581 | uncertain significance | Cardiovascular phenotype | 2024-03-11 | criteria provided, single submitter | clinical testing | The p.K860E variant (also known as c.2578A>G), located in coding exon 20 of the MYH7 gene, results from an A to G substitution at nucleotide position 2578. The lysine at codon 860 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 variant has been reported in individuals with hypertrophic cardiomyopathy (HCM); however, clinical details were limited (Ambry internal data; Burns C et al. Circ Cardiovasc Genet, 2017 Aug;10:). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |