Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000183079 | SCV000235488 | likely pathogenic | not provided | 2016-02-04 | criteria provided, single submitter | clinical testing | The Y1495S likely pathogenic variant in the SCN5A gene has been reported in one individual with LQTS and it was absent from approximately 2,600 control alleles (Kapplinger et al., 2009). In addition, Ahern et al. (2005) reported that SCN5A sodium channel inactivation is mediated by phosphorylation of tyrosine residues and the Tyrosine 1495 residue is a preferred phosphorylation site. As a result, mutation of the Tyrosine 1495 residue to Y1495F significantly altered phosphorylation and consequently sodium channel inactivation (Ahern et al., 2005). The Y1495S variant is a semi-conservative substitution of one neutral, polar amino acid with another, and the Y1495 residue is conserved across species. Furthermore, Y1495S was not observed in approximately 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. |
| Invitae | RCV000183079 | SCV001505356 | uncertain significance | not provided | 2023-11-06 | criteria provided, single submitter | clinical testing | This sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 1495 of the SCN5A protein (p.Tyr1495Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of long QT syndrome (PMID: 19716085, 25904541). ClinVar contains an entry for this variant (Variation ID: 67900). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. |
| Cardiovascular Biomedical Research Unit, |
RCV000058680 | SCV000090200 | not provided | Congenital long QT syndrome | no assertion provided | literature only | This variant has been reported as associated with Long QT syndrome in the following publications (PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. |