ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.3688G>A (p.Glu1230Lys) (rs199473598)

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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 RCV000058587 SCV000090107 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:15840476). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
GeneDx RCV000183184 SCV000235601 pathogenic not provided 2011-11-11 criteria provided, single submitter clinical testing p.Glu1231Lys in the SCN5A gene; disease-causing mutation (Tester D et al. 2008). TheG>A nucleotide substitution in exon 21 of the SCN5A gene, results in replacement of the normal Glutamic acid codon (GAG) with a Lysine codon (AAG) at amino acid position 1231 in the cardiac sodium voltage-gated channel, type V-a. This missense change is denoted p.Glu1231Lys (aka E1231K) at the protein level and c.3691 G>A at the cDNA level. The Glu1231Lys mutation has been reported in association with LQTS (Tester D et al. 2008). Tester et al. reported Glu1231Lys in one patient with LQTS and did not observe it in more than 1,500 control alleles. This mutation also was not observed in up to 400 control alleles from individuals of African American and Caucasian ancestry tested at GeneDx, indicating it is not a common benign polymorphsim. Glu1231Lys results in a non-conservative amino acid substitution of a negatively charged Glutamic acid with a positively charged Lysine residue at a position that is class conserved. Furthermore, mutations in surrounding codons (Tyr1228His, Arg1232Gln, Lys1236Arg, Lys1236Asn, Leu1239Pro) have been reported in association with Brugada syndrome, further supporting the functional importance of this region of the protein. The variant is found in LQT panel(s).
Invitae RCV000797942 SCV000937530 uncertain significance Brugada syndrome 2018-11-30 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 1231 of the SCN5A protein (p.Glu1231Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual referred for long QT syndrome genetic testing (PMID: 15840476). ClinVar contains an entry for this variant (Variation ID: 67812). 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: "Benign"; Align-GVGD: "Class C0"). 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.

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