ClinVar Miner

Submissions for variant NM_000335.5(SCN5A):c.3619G>A (p.Glu1207Lys)

gnomAD frequency: 0.00001  dbSNP: rs774537241
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV001842611 SCV001360240 uncertain significance Cardiac arrhythmia 2018-12-10 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the transmembrane domain DIII of the SCN5A protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. An experimental study has shown that this variant causes abnormal electrophysiological phenotype in cells (PMID: 25904541). This variant has been reported in an individual affected with long QT syndrome (PMID: 25904541). This variant has also been identified in 3/242868 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
GeneDx RCV001092239 SCV001987707 uncertain significance not provided 2019-07-03 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Identified in an individual with long QT syndrome type 3, but familial segregation information and additional clinical information were not included (Wild et al., 2016); This variant is associated with the following publications: (PMID: 25904541, 29728395, 27566755, 30662450)
Ambry Genetics RCV004986806 SCV005500144 uncertain significance Cardiovascular phenotype 2024-08-26 criteria provided, single submitter clinical testing The p.E1208K variant (also known as c.3622G>A), located in coding exon 19 of the SCN5A gene, results from a G to A substitution at nucleotide position 3622. The glutamic acid at codon 1208 is replaced by lysine, an amino acid with similar properties. This variant has been reported in a long QT syndrome cohort, but clinical details were limited (Goldenberg I et al. J Am Coll Cardiol, 2011 Jan;57:51-9; Wilde AA et al. Circulation, 2016 Sep;134:872-82). Functional studies by one group suggest this variant may have some impact on channel function; however, additional evidence is needed to confirm these findings (Kapplinger JD et al. Circ Cardiovasc Genet, 2015 Aug;8:582-95). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.

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