Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000620538 | SCV000737889 | uncertain significance | Cardiovascular phenotype | 2017-01-23 | criteria provided, single submitter | clinical testing | The p.M1766I variant (also known as c.5298G>A), located in coding exon 27 of the SCN5A gene, results from a G to A substitution at nucleotide position 5298. The methionine at codon 1766 is replaced by isoleucine, an amino acid with highly similar properties. Other alterations affecting the same amino acid have been reported in association with SCN5A-related arrhythmia (Valdivia CR et al. Cardiovasc. Res., 2002 Aug;55:279-89; Mullally J et al. Heart Rhythm, 2013 Mar;10:378-82; Savastano S et al. Heart Rhythm, 2014 Jul;11:1176-83). 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. |
| Labcorp Genetics |
RCV003656130 | SCV001377223 | pathogenic | not provided | 2020-12-23 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Met1766 amino acid residue in SCN5A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12123767). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with clinical features of SCN5A-related conditions (Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 519384). This sequence change replaces methionine with isoleucine at codon 1766 of the SCN5A protein (p.Met1766Ile). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and isoleucine. |