ClinVar Miner

Submissions for variant NM_006514.3(SCN10A):c.472T>G (p.Tyr158Asp) (rs202192818)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000547184 SCV000637027 uncertain significance Brugada syndrome 2019-09-20 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with aspartic acid at codon 158 of the SCN10A protein (p.Tyr158Asp). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and aspartic acid. This variant is present in population databases (rs202192818, ExAC 0.05%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals affected with atrial fibrillation and arrhythmogenic right ventricular dysplasia/cardiomyopathy (PMID: 25053638, 25085921, 26733327). All reported individuals also carried another change (c.2441G>A, p.Arg814His) that was shown to be in cis in at least three individuals (PMID: 25053638, 26733327). ClinVar contains an entry for this variant (Variation ID: 463260). Experimental studies in vitro have shown that this missense change generates a peak current that is 2 times larger than that of wild type (PMID: 25053638). 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.
Fulgent Genetics,Fulgent Genetics RCV000764505 SCV000895576 uncertain significance Episodic pain syndrome, familial, 2 2018-10-31 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000998052 SCV001153923 uncertain significance not provided 2018-10-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000764505 SCV001159807 uncertain significance Episodic pain syndrome, familial, 2 2018-07-13 criteria provided, single submitter clinical testing The p.Tyr158Asp has been reported on the same chromosome together with p. Arg814His, constituting a complex variant p.[Tyr158Asp, Arg814His] in several adult individuals with atrial fibrillation/polarization abnormality (Savio-Galimberti 2014, Jabbari 2015, Te Riele 2016). The Tyr158Asp and Arg814His variants were also identified in the study of patients with AV nodal reentrant tachycardia (Andreasen 2018). Savio-Galimberti et al. (2014) reported two families with possible variable penetrance and also showed that that these variants were associated with 2- and 4-fold increase in peak currents in a transient transfection and expression experiments in ND7/23 cells. Both Tyr158Asp and Arg814His variants are listed in gnomAD at population frequencies 0.04 and 0.05%, higher than expected for a pathogenic variant (Kobayashi 2017). Both variants are listed in ClinVar with current classification of uncertain significance (Variant ID 463260 and 420025). Thus, based on the available evidence, the complex variant p.[Tyr158Asp, Arg814His] was classified as of uncertain significance.

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