Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000158674 | SCV000208609 | pathogenic | not provided | 2014-01-23 | criteria provided, single submitter | clinical testing | p.Glu1619Lys (GAA>AAA): c.4855 G>A in exon 34 of the MYH7 gene (NM_000257.2). The E1619K mutation in the MYH7 gene has been reported in one child with onset of cardiomyopathy at one month of age (Hershberger R et al., 2008; Rampersaud E et al., 2011). The father, paternal aunt, and two paternal cousins once removed were reported to have DCM, however these individuals were not available for genetic testing (Rampersaud E et al., 2011). E1619K 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. The E1619 residue is highly conserved across species. Mutations in nearby residues (R1608P, R1634C) have been reported in association with cardiomyopathy, further supporting the functional importance of this region of the protein. Additionally, the E1619K mutation was not observed inapproximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, E1619K in the MYH7 gene is interpreted as a disease-causing mutation. The variant is found in DCM-CRDM panel(s). |
| Invitae | RCV000473596 | SCV000546263 | uncertain significance | Hypertrophic cardiomyopathy | 2016-10-23 | criteria provided, single submitter | clinical testing | In summary this variant is a rare sequence change with an uncertain effect on protein function, without additional functional and/or genetic data, this variant has been classified as a variant of Uncertain Significance. 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 has been reported in an individual affected with dilated cardiomyopathy. Currently there is insufficient evidence to conclude whether this variant segregates with disease or not (PMID: 21483645). This variant was also reported in an individual affected with motor neuropathy (PMID: 27387980). However, one pathogenic allele was identified in the MYH7 gene, which suggests that this c.4855G>A substitution in MYH7 was not the primary cause of disease in this individual, ClinVar contains an entry for this variant (Variation ID: 181268). This variant is not present in population databases (ExAC no frequency) . This sequence change replaces glutamic acid with lysine at codon 1619 of the MYH7 protein (p.Glu1619Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. |