Submissions for variant NM_000335.5(SCN5A):c.3971A>G (p.Asn1324Ser)

dbSNP: rs28937317

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003234898	SCV001397968	pathogenic	not provided	2024-04-06	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 1325 of the SCN5A protein (p.Asn1325Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with long QT syndrome (PMID: 8541846, 17905336, 28412158; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 9370). 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. Experimental studies have shown that this missense change affects SCN5A function (PMID: 8620612, 8917568, 19762097). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002354154	SCV002623130	likely pathogenic	Cardiovascular phenotype	2024-10-15	criteria provided, single submitter	clinical testing	The p.N1325S variant (also known as c.3974A>G), located in coding exon 22 of the SCN5A gene, results from an A to G substitution at nucleotide position 3974. The asparagine at codon 1325 is replaced by serine, an amino acid with highly similar properties. This alteration has been reported in multiple long QT syndrome (LQTS) cohorts and has been reported to segregate with disease in a large family (Wang Q, Hum. Mol. Genet. 1995 Sept;4(9):1603-7; Splawski I, Circulation 2000 Sep; 102(10):1178-85; Tester DJ, Heart Rhythm 2005 May; 2(5):507-17; Yong SL, Biochem. Biophys. Res. Commun. 2007 Jan; 352(2):378-83; Chung SK, Heart Rhythm 2007 Oct; 4(10):1306-14; Kapplinger JD, Heart Rhythm 2009 Sep; 6(9):1297-303). In addition, this alteration has been shown to have an impact on sodium channel current (Dumaine R, Circ. Res. 1996 May; 78(5):916-24; Tian XL, Cardiovasc. Res. 2004 Feb;61(2):256-67; Yong SL, Biochem. Biophys. Res. Commun. 2007 Jan; 352(2):378-83). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx	RCV003234898	SCV003933403	pathogenic	not provided	2023-06-13	criteria provided, single submitter	clinical testing	Identified in patients with LQTS referred for genetic testing at GeneDx and in published literature (Wang et al., 1995; Splawski et al., 2000; Tester et al., 2005; Yong et al., 2007; Chung et al., 2007; Kapplinger et al., 2009; Anderson et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect using patch clamp studies that showed that N1325S results in abnormal channel current, and N1325S mouse cardiomyocytes showed contractile dysfunction, possibly caused by aberrant cardiomyocyte apoptosis (Dumaine et al., 1996; Wang et al., 1996; Tian et al., 2004; Yong et al., 2007; Zhang et al., 2011); 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: 14736542, 8541846, 19762097, 8917568, 10973849, 19716085, 17118339, 17490620, 17157817, 21677263, 17905336, 8620612, 15840476, 28412158)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000009964	SCV005398136	pathogenic	Long QT syndrome 3	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are both known mechanisms of disease in this gene. Loss of function is usually associated with Brugada syndrome 1 (MIM#601144) and sick sinus syndrome (SSS) (MIM#608567), whereas gain of function is usually associated with long QT syndrome (LQTS) (MIM#603830). Dilated cardiomyopathy 1E (DCM) (MIM#601154) can be caused by variants with either a loss- or gain of function mechanism (PMID: 29798782). However, some variants simultaneously result in both a loss- and gain of function effect, and have been observed in patients with LQTS, Brugada syndrome or SSS, and patients with a blended phenotype. Additionally, different studies have shown conflicting mechanisms in association with atrial fibrillation (MIM#614022) (PMIDs: 29806494, 19167345, 26798387). (I) 0108 - This gene is associated with both recessive and dominant disease. Most conditions associated with this gene are dominantly inherited; however SSS can be caused by recessive variants (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance. Among individuals with an SCN5A pathogenic variant, approximately 20%-30% have an ECG diagnostic of Brugada syndrome and approximately 80% manifest the characteristic ECG changes when challenged with a sodium channel blocker (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to serine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated DIII-S4/S5 domain (PMID: 27566755). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in at least twenty individuals with LQTS or LQT3. (ClinVar, PMIDs: 17905336, 27566755, 32848785). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Compared to WT cells, HEK293 cells transfected with the p.(Asn1325Ser) mutant transcript demonstrated both increased availability of mutant channels and late sodium current which were reversed when treated with the sodium current inhibitor, mexiletine. However, patch clamp assays have been shown to be unreliable; therefore results from these studies are used with caution during variant classification (PMID: 32848785). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000009964	SCV000030185	pathogenic	Long QT syndrome 3	1995-03-10	no assertion criteria provided	literature only
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058618	SCV000090138	not provided	Congenital long QT syndrome		no assertion provided	literature only	This variant has been reported as associated with Long QT syndrome in the following publications (PMID:8541846;PMID:14736542;PMID:15840476;PMID:17905336;PMID:19716085;PMID:19841300;PMID:19762097;PMID:8620612;PMID:8917568). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.