ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.3695G>A (p.Arg1232Gln) (rs199473206)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183043 SCV000235452 uncertain significance not provided 2017-04-05 criteria provided, single submitter clinical testing The R1232Q variant in the SCN5A gene has been reported in one individual with suspected Brugada syndrome and was absent in >2,600 control alleles (Kapplinger et al., 2010). However, specific clinical information was not provided and segregation studies were not performed (Kapplinger et al., 2010). A different variant involving the same residue, R1232W, was identified in cis with the T1620M variant in a family with ventricular fibrillation and functional studies in Xenopus oocytes showed an impact on sodium channel kinetics (Chen et al., 1998; Vilin et al., 2001). Baroudi et al. later demonstrated that R1232W/T1620M expression in tsA201 cells resulted in a lack of sodium current and protein retention in the endoplasmic reticulum (ER) which was rescued when R1232W was replaced with R1232K (Baroudi et al., 2008). Based on this, the authors proposed that a positively charged amino acid at R1232 is necessary for proper plasma membrane localization (Baroudi et al., 2008). However, a subsequent study in Hek293 cells did not observe an effect on sodium channel function or localization (Makita et al., 2008). The R1232Q variant 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. The R1232Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position where only amino acids with similar properties to Arginine are tolerated across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, missense variants in nearby residues (Y1228H, E1231K, K1236N, L1239P) have been reported in the Human Gene Mutation Database in association with arrhythmia (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000058589 SCV000815993 uncertain significance Brugada syndrome 2018-03-16 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1232 of the SCN5A protein (p.Arg1232Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs199473206, ExAC 0.01%). This variant has been reported in an individual referred for testing for Brugada syndrome (PMID: 20129283). ClinVar contains an entry for this variant (Variation ID: 67814). 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 and their clinical significance is uncertain. 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.
Color RCV001177677 SCV001341930 uncertain significance Arrhythmia 2019-12-02 criteria provided, single submitter clinical testing
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058589 SCV000090109 not provided Brugada syndrome no assertion provided literature only This variant has been reported as associated with Brugada syndrome in the following publications (PMID:20129283). 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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