Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000429496 | SCV000536636 | likely pathogenic | not provided | 2017-02-08 | criteria provided, single submitter | clinical testing | The D717N variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The D717N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (G716R, R719Q, R719QW, R719P) have been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014), supporting the functional importance of this region of the protein. However, this variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity. |
| Invitae | RCV000460699 | SCV000546241 | likely pathogenic | Hypertrophic cardiomyopathy | 2022-11-14 | criteria provided, single submitter | clinical testing | 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. This variant disrupts the p.Asp717 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25558701, 25935763). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 393254). This variant has not been reported in the literature in individuals affected with MYH7-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 717 of the MYH7 protein (p.Asp717Asn). |
| Ambry Genetics | RCV002429463 | SCV002730421 | uncertain significance | Cardiovascular phenotype | 2019-02-21 | criteria provided, single submitter | clinical testing | The p.D717N variant (also known as c.2149G>A), located in coding exon 17 of the MYH7 gene, results from a G to A substitution at nucleotide position 2149. The aspartic acid at codon 717 is replaced by asparagine, an amino acid with highly similar properties. An alternate amino acid at this position, p.D717G, has been reported in a family with multiple affected carriers with hypertrophic cardiomyopathy (HCM) (García-Giustiniani D et al. Heart, 2015 Jul;101:1047-53). This amino acid position is highly 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. |