ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.3694C>T (p.Arg1232Trp) (rs199473207)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183042 SCV000235451 uncertain significance not provided 2015-09-03 criteria provided, single submitter clinical testing There is conflicting evidence regarding the Arg1232Trp variant in the SCN5A gene. Arg1232Trp has been reported previously in multiple unrelated individuals with Brugada syndrome, sometimes in addition to the Thr1620Met mutation in the SCN5A gene (Chen Q et al., 1998; Baroudi G et al., 2002; Kapplinger J et al., 2009; Meregalli P et al., 2009; Makita N et al., 2008; Nakajima T et al., 2011). Chen Q et al. (1998) identified the Arg1232Trp variant in one family with idiopathic ventricular fibrillation, who also harbored the Thr1620Met mutation on the same SCN5A allele (in cis). Functional studies suggested that Thr1620Met is probably a disease causing mutation and that Arg1232Trp is a possible rare polymorphism since it did not alter the current voltage activity of the sodium channel. Another functional study identified that the presence of a positively charged amino acid at position 1232 was essential for the proper trafficking of the sodium channel protein to the cell surface, and that the double mutant (Arg1232Trp/Thr1620Met) showed an abnormal functional sodium channel expression (Baroudi G et al., 2002). However, Makita N et al. (2008) reported Arg1232Trp/Thr1620Met did not affect protein trafficking in their expression studies, contradicting the functional effect reported by Baroudi G et al. (2002). Arg1232Trp results in a non-conservative amino acid substitution of a positively charged Arginine with a neutral, non-polar Tryptophan, located between the S1-S2 extracellular loop of domain III. Arg1232Trp was not observed in >1,300 control individuals studied (Chen Q et al., 1998; Kapplinger J et al., 2010) and was not observed in up to 600 alleles from control individuals of Caucasian and African American ancestry tested at GeneDx. The NHLBI ESP Exome Variant Server reports Arg1232Trp was not observed in approximately 6,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Another mutation in this codon (Arg1232Gln) and mutations in neighboring codons (Tyr1228His, Glu1231Lys, Lys1236Arg) have been reported in association with Brugada syndrome and LQTS, supporting the functional importance of this region of the protein.In summary, with the clinical and molecular information available at this time, we cannot determine whether the Arg1232Trp variant is a disease-causing mutation or a benign variant. The variant is found in BRUGADA panel(s).
Color RCV001185988 SCV001352308 uncertain significance Arrhythmia 2019-02-26 criteria provided, single submitter clinical testing
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058588 SCV000090108 not provided Brugada syndrome no assertion provided literature only This variant has been reported as associated with Brugada syndrome in the following publications (PMID:9521325;PMID:19251209;PMID:20129283;PMID:21321465). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
GeneReviews RCV000144030 SCV000188923 pathogenic Brugada syndrome 1 2014-04-10 no assertion criteria provided literature only

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