ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.787G>A (p.Val263Ile) (rs752824646)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182947 SCV000235344 uncertain significance not provided 2017-01-20 criteria provided, single submitter clinical testing p.Val263Ile (GTC>ATC): c.787 G>A in exon 7 of the SCN5A gene (NM_198056.2) The V263I variant in the SCN5A gene has not been reported as a disease-causing variant or as a benign polymorphism to our knowledge. Although V263I results in a conservative amino acid substitution of one non-polar amino acid for another, this substitution occurs at a position that is conserved across species. In silico analysis predicts V263I is probably damaging to the protein structure/function. Variants in nearby residues (I267L, Q270K) have been reported in association with arrhythmia, further supporting the functional importance of this region of the protein. Furthermore, the NHLBI Exome Sequencing Project reports V263I was not observed in approximately 6,500 individuals of European and African American ancestry, indicating it is not a common benign variant in these populations. Based on the currently available information, it is unclear whether this is a pathogenic variant or a rare benign variant. The variant is found in BRUGADA,LQT panel(s).
Illumina Clinical Services Laboratory,Illumina RCV000319650 SCV000444189 uncertain significance Paroxysmal familial ventricular fibrillation 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000374434 SCV000444190 uncertain significance Long QT syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000279922 SCV000444191 uncertain significance Progressive familial heart block 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000334721 SCV000444192 uncertain significance Sick sinus syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000389273 SCV000444193 uncertain significance Dilated Cardiomyopathy, Dominant 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000294829 SCV000444194 uncertain significance Romano-Ward syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000349715 SCV000444195 uncertain significance Brugada syndrome 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000349715 SCV000760281 uncertain significance Brugada syndrome 2018-11-15 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 263 of the SCN5A protein (p.Val263Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs752824646, ExAC 0.009%). This variant has not been reported in the literature in individuals with SCN5A-related disease. ClinVar contains an entry for this variant (Variation ID: 201444). 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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