Submissions for variant NM_000335.5(SCN5A):c.2399G>A (p.Arg800His)

gnomAD frequency: 0.00001  dbSNP: rs566251672

Total submissions: 7

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
Labcorp Genetics (formerly Invitae), Labcorp	RCV003539817	SCV000291792	uncertain significance	not provided	2023-09-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 800 of the SCN5A protein (p.Arg800His). 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. Experimental studies have shown that this missense change affects SCN5A function (PMID: 32323320). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 222807). This missense change has been observed in individual(s) with clinical features of long QT syndrome (PMID: 26159999, 32323320). This variant is present in population databases (rs566251672, gnomAD 0.004%).
Fulgent Genetics, Fulgent Genetics	RCV000765739	SCV000897107	uncertain significance	Brugada syndrome 1; Long QT syndrome 3; Sick sinus syndrome 1; Progressive familial heart block, type 1A; Ventricular fibrillation, paroxysmal familial, type 1; Dilated cardiomyopathy 1E; SUDDEN INFANT DEATH SYNDROME; Atrial fibrillation, familial, 10	2018-10-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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.
Color Diagnostics, LLC DBA Color Health	RCV001842961	SCV001734467	uncertain significance	Cardiac arrhythmia	2023-02-23	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 800 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). An in vitro functional study has shown that this variant causes a shorter recovery time from inactivation in the mutant channel (PMID: 32323320). This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 26281194) and in another individual with short-coupled variant of torsades de pointes (PMID: 32323320). This variant has been identified in 5/279914 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002444836	SCV002732002	uncertain significance	Cardiovascular phenotype	2022-07-26	criteria provided, single submitter	clinical testing	The p.R800H variant (also known as c.2399G>A), located in coding exon 14 of the SCN5A gene, results from a G to A substitution at nucleotide position 2399. The arginine at codon 800 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in an exome cohort and in an individual with features of hypertrophic cardiomyopathy (HCM), who also carried a variant in another cardiac-related gene (Ghouse J et al. Eur. Heart J., 2015 Oct;36:2523-9; Josifovska S et al. Biotechnology & Biotechnological Equipment. 2018 Feb;679-685). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV001842961	SCV004820348	uncertain significance	Cardiac arrhythmia	2023-11-28	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 800 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). An in vitro functional study has shown that this variant causes a shorter recovery time from inactivation in the mutant channel (PMID: 32323320). This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 26281194) and in another individual with short-coupled variant of torsades de pointes (PMID: 32323320). This variant has been identified in 5/279914 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.