Submissions for variant NM_000335.5(SCN5A):c.5473C>T (p.Arg1825Cys)

gnomAD frequency: 0.00001  dbSNP: rs199473635

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000183122	SCV000235533	uncertain significance	not provided	2024-06-13	criteria provided, single submitter	clinical testing	Reported previously in one individual with a history of atrial fibrillation, coronary artery disease and hypertension but familial segregation information was not included (PMID: 18378609); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23838598, 25175087, 18378609)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000183122	SCV000637181	uncertain significance	not provided	2025-01-23	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1826 of the SCN5A protein (p.Arg1826Cys). This variant is present in population databases (rs199473635, gnomAD 0.01%). This missense change has been observed in individual(s) with atrial fibrillation (PMID: 18378609). ClinVar contains an entry for this variant (Variation ID: 67994). 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 disruptive. 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	RCV001842386	SCV001342180	uncertain significance	Cardiac arrhythmia	2019-06-13	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 1826 of the SCN5A protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in an individual affected with paroxysmal atrial fibrillation (PMID: 18378609) and in a healthy control individual (PMID: 25904541). This variant has also been identified in 6/280984 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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	RCV004019061	SCV004944532	uncertain significance	Cardiovascular phenotype	2022-08-11	criteria provided, single submitter	clinical testing	The c.5476C>T (p.R1826C) alteration is located in exon 28 (coding exon 27) of the SCN5A gene. This alteration results from a C to T substitution at nucleotide position 5476, causing the arginine (R) at amino acid position 1826 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV001842386	SCV005428218	uncertain significance	Cardiac arrhythmia	2024-08-06	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 1826 of the SCN5A protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. This variant is found within a highly conserved C-terminal region (a.a. 1773-2016). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with Brugada syndrome (PMID: 32893267). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with paroxysmal atrial fibrillation (PMID: 18378609) and in one healthy control individual (PMID: 25904541). This variant has been identified in 6/280984 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.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058785	SCV000090305	not provided	Atrial fibrillation		no assertion provided	literature only	This variant has been reported as associated with Atrial fibrillation in the following publications (PMID:18378609). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.