rs28937317
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong
The NM_000335.5(SCN5A):āc.3971A>Gā(p.Asn1324Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,459,700 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā ā ).
Frequency
Consequence
NM_000335.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SCN5A | NM_001099404.2 | c.3974A>G | p.Asn1325Ser | missense_variant | Exon 23 of 28 | ENST00000413689.6 | NP_001092874.1 | |
SCN5A | NM_000335.5 | c.3971A>G | p.Asn1324Ser | missense_variant | Exon 23 of 28 | ENST00000423572.7 | NP_000326.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.3974A>G | p.Asn1325Ser | missense_variant | Exon 23 of 28 | 5 | NM_001099404.2 | ENSP00000410257.1 | ||
SCN5A | ENST00000423572.7 | c.3971A>G | p.Asn1324Ser | missense_variant | Exon 23 of 28 | 1 | NM_000335.5 | ENSP00000398266.2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 0.00000206 AC: 3AN: 1459700Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 725988
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:2
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. -
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) -
Long QT syndrome 3 Pathogenic:2
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 -
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Cardiovascular phenotype Pathogenic:1
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. -
Congenital long QT syndrome Other:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at