ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.4000A>G (p.Ile1334Val) (rs199473226)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183057 SCV000235466 pathogenic not provided 2013-05-30 criteria provided, single submitter clinical testing The Ile1334Val mutation in the SCN5A gene has been reported in two unrelated individuals with LQTS, and it was absent from 2,600 reference alleles (Kapplinger J et al., 2009; Stattin E et al., 2012). Also, the NHLBI Exome Sequencing Project reports Ile1334Val was not observed in approximately 6,500 individuals of European and African American ancestry, indicating it is not a common benign variant in these populations. Although Ile1334Val results in a conservative amino acid substitution of one non-polar amino acid with another, the Ile1334 residue is conserved across species. Mutations in nearby residues (Ala1332Thr, Pro1332Leu, Ser1333Tyr) have been reported in association with LQTS, further supporting the functional importance of this region of the protein. The variant is found in LQT panel(s).
Invitae RCV000456774 SCV000545050 uncertain significance Brugada syndrome 2016-08-24 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 1334 of the SCN5A protein (p.Ile1334Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs199473226, ExAC 0.002%). This variant was reported in individuals referred for long QT testing (PMID: 19716085, 23098067). ClinVar contains an entry for this variant (Variation ID: 67847). This variant identified in the SCN5A gene is located in the transmembrane spanning DIII-S4/S5 region of the resulting protein (PMID: 25348405), but it is unclear how this variant impacts the function of this protein. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. It has been reported in both the general population and individuals referred for longQT testing, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058626 SCV000090146 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.

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