Submissions for variant NM_000335.5(SCN5A):c.1703G>A (p.Arg568His)

gnomAD frequency: 0.00003  dbSNP: rs199473125

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000476617	SCV000545087	uncertain significance	Brugada syndrome	2021-09-30	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with histidine at codon 568 of the SCN5A protein (p.Arg568His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs199473125, ExAC 0.03%). This variant has been observed in individual(s) with long QT syndrome (PMID: 27287068). ClinVar contains an entry for this variant (Variation ID: 67679). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). Experimental studies have shown that this variant affects SCN5A protein function (PMID: 27287068). 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.
Color Diagnostics, LLC DBA Color Health	RCV001842292	SCV001350210	uncertain significance	Cardiac arrhythmia	2023-10-02	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 568 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). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with long QT syndrome, as well as in two unaffected family members of the family (PMID: 27287068) and in a second individual with long QT syndrome (PMID: 32893267). This variant has also been identified in 6/280398 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.
Fulgent Genetics, Fulgent Genetics	RCV002490652	SCV002785462	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	2021-08-11	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001842292	SCV004824157	uncertain significance	Cardiac arrhythmia	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 568 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). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with long QT syndrome, as well as in two unaffected family members of the family (PMID: 27287068) and in a second individual with long QT syndrome (PMID: 32893267). This variant has also been identified in 6/280398 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	RCV004019036	SCV004943818	uncertain significance	Cardiovascular phenotype	2022-06-09	criteria provided, single submitter	clinical testing	The c.1703G>A (p.R568H) alteration is located in exon 12 (coding exon 11) of the SCN5A gene. This alteration results from a G to A substitution at nucleotide position 1703, causing the arginine (R) at amino acid position 568 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058443	SCV000089963	not provided	not provided		no assertion provided	literature only	This variant has been reported in the following publications (PMID:20129283;PMID:19841300).