ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.3410A>C (p.Glu1137Ala) (rs199473198)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058570 SCV000090090 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:19862833). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
GeneDx RCV000183036 SCV000235444 likely pathogenic not provided 2014-07-28 criteria provided, single submitter clinical testing p.E1138A was reported previously in one individual with Romano-Ward syndrome (Hedley P et al., 2009). The E1138A variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The E1138A variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Missense mutations in nearby residues (T1131I, S1140T) have been reported in association with arrhythmia, supporting the functional importance of this region of the protein. Nevertheless, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded.The variant is found in LQT panel(s).
Invitae RCV000472805 SCV000545075 uncertain significance Brugada syndrome 2016-11-08 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with alanine at codon 1138 of the SCN5A protein (p.Glu1138Ala). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and alanine. This variant is not present in population databases (rs199473198, ExAC no frequency). This variant has been reported in an individual affected with long QT syndrome (PMID: 19862833). ClinVar contains an entry for this variant (Variation ID: 67796). This variant identified in the SCN5A gene is located in the interdomain linker DII/DIII 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. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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