ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.3574C>T (p.Arg1192Trp) (rs192379242)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000624561 SCV000742576 uncertain significance Inborn genetic diseases 2017-06-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: UNCERTAIN: Alteration(s) of Uncertain Clinical Significance Detected
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000239165 SCV000297011 uncertain significance Long QT syndrome 3; Brugada syndrome 2015-09-09 criteria provided, single submitter clinical testing
GeneDx RCV000183039 SCV000235448 uncertain significance not provided 2017-01-31 criteria provided, single submitter clinical testing The R1193W variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The R1193W variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The R1193W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is mostly conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense mutations in nearby residues (A1186T, R1195H, Y1199S) have been reported in association with arrhythmia, supporting the functional importance of this region of the protein. Nevertheless, the 1000 Genomes Project reports R1193W was observed in 0.5% (1 in 192) alleles from individuals of a sub-population of Asian background. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant.
Invitae RCV000470436 SCV000545086 uncertain significance Brugada syndrome 2017-09-17 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 1193 of the SCN5A protein (p.Arg1193Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs192379242, ExAC 0.06%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with SCN5A-related disease. ClinVar contains an entry for this variant (Variation ID: 201497). 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.

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