Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000035915 | SCV000059566 | uncertain significance | not specified | 2015-11-20 | criteria provided, single submitter | clinical testing | proposed classification - variant undergoing re-assessment, contact laboratory |
| Gene |
RCV000225735 | SCV000208594 | likely pathogenic | not provided | 2015-09-30 | criteria provided, single submitter | clinical testing | p.Glu1496Ala (GAG>GCG): c.4487 A>C in exon 32 of the MYH7 gene (NM_000257.2). The E1496A mutation in the MYH7 gene has been previously reported in one individual with HCM and the mutation was absent from 168 control individuals (Zeller R et al., 2006). Furthermore, the E1496A mutation was not observed inapproximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The E1496A variant is a non-conservative amino acid substitution as these residues differ in polarity, charge, size and/or other properties and is more likely to impact secondary structure. Mutations in nearby residues (Y1488C, S1491C, R1500W) have been reported in association with cardiomyopathy, further supporting the functional importance of this region of the protein. In summary, E1496A in the MYH7 gene is interpreted as a disease-causing mutation. The variant is found in HCM panel(s). |
| Blueprint Genetics | RCV000225735 | SCV000927397 | likely pathogenic | not provided | 2017-09-06 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV001209343 | SCV001380773 | pathogenic | Hypertrophic cardiomyopathy | 2023-10-03 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 1496 of the MYH7 protein (p.Glu1496Ala). This variant is present in population databases (rs397516218, gnomAD 0.002%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 16715312, 24793961; Invitae). ClinVar contains an entry for this variant (Variation ID: 43021). 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. For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV002326732 | SCV002637491 | uncertain significance | Cardiovascular phenotype | 2022-06-01 | criteria provided, single submitter | clinical testing | The p.E1496A variant (also known as c.4487A>C), located in coding exon 30 of the MYH7 gene, results from an A to C substitution at nucleotide position 4487. The glutamic acid at codon 1496 is replaced by alanine, an amino acid with dissimilar properties. This alteration has been reported in hypertrophic cardiomyopathy (HCM) cohorts; however, clinical details were limited (Zeller R et al. J Mol Med (Berl), 2006 Aug;84:682-91; Bos JM et al. Mayo Clin Proc, 2014 Jun;89:727-37; Hathaway J et al. BMC Cardiovasc Disord, 2021 03;21:126). 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. |