rs28937317
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong
The NM_001099404.2(SCN5A):āc.3974A>Gā(p.Asn1325Ser) 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 ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1325K) has been classified as Uncertain significance.
Frequency
Consequence
NM_001099404.2 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/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN5A | NM_001099404.2 | c.3974A>G | p.Asn1325Ser | missense_variant | 23/28 | ENST00000413689.6 | |
SCN5A | NM_000335.5 | c.3971A>G | p.Asn1324Ser | missense_variant | 23/28 | ENST00000423572.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.3974A>G | p.Asn1325Ser | missense_variant | 23/28 | 5 | NM_001099404.2 | P4 | |
SCN5A | ENST00000423572.7 | c.3971A>G | p.Asn1324Ser | missense_variant | 23/28 | 1 | NM_000335.5 | A1 |
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
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 13, 2023 | 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) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 30, 2023 | 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. - |
Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 16, 2023 | 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. - |
Long QT syndrome 3 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 10, 1995 | - - |
Congenital long QT syndrome Other:1
not provided, no classification provided | literature only | Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust | - | 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