ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.2399G>A (p.Arg800His) (rs566251672)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000208238 SCV000264207 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2015-03-26 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000765739 SCV000897107 uncertain significance Brugada syndrome 1; Long QT syndrome 3; Sick sinus syndrome 1, autosomal recessive; Progressive familial heart block type 1A; Paroxysmal familial ventricular fibrillation 1; Dilated cardiomyopathy 1E; SUDDEN INFANT DEATH SYNDROME; Atrial fibrillation, familial, 10 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780704 SCV000918197 uncertain significance not specified 2018-09-24 criteria provided, single submitter clinical testing Variant summary: SCN5A c.2399G>A (p.Arg800His) results in a non-conservative amino acid change located in the Ion transport domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.8e-05 in 276510 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2399G>A has been reported in the literature in individuals affected with Arrhythmia (Ghouse_2015, Josifovska_2018). In particular, one patient with a rare form of asymmetrical left ventricle hypertrophy with mild left ventricular outflow obstruction (intra-ventricle gradient) was found to be digenic carrying the variant of interest, along with another CACNA1C variant, p.Arg514Gly. The child's parent carried the variant of interest and was indicated to be unaffected (Josifovska_2018). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000232921 SCV000291792 uncertain significance Brugada syndrome 2018-12-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 800 of the SCN5A protein (p.Arg800His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs566251672, ExAC 0.003%). This variant has not been reported in the literature in individuals with SCN5A-related disease. ClinVar contains an entry for this variant (Variation ID: 222807). 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 tolerated, 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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