rs199473298
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP2PP3_StrongPP5
The NM_001099404.2(SCN5A):c.5134G>A(p.Gly1712Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,888 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1712D) 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 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN5A | NM_001099404.2 | c.5134G>A | p.Gly1712Ser | missense_variant | 28/28 | ENST00000413689.6 | |
SCN5A | NM_000335.5 | c.5131G>A | p.Gly1711Ser | missense_variant | 28/28 | ENST00000423572.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.5134G>A | p.Gly1712Ser | missense_variant | 28/28 | 5 | NM_001099404.2 | P4 | |
SCN5A | ENST00000423572.7 | c.5131G>A | p.Gly1711Ser | missense_variant | 28/28 | 1 | NM_000335.5 | A1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251432Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135904
GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461888Hom.: 0 Cov.: 35 AF XY: 0.00000688 AC XY: 5AN XY: 727244
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
not provided Pathogenic:2Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | SCN5A: PM1, PM2, PM5, PS4:Moderate, PP3, PS3:Supporting - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 14, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in a patient referred for Brugada syndrome (BrS) genetic testing and in a single family with histories of cardiac arrest, incomplete bundle branch block and amjaline- induced BrS (Kapplinger et al., 2010; Walsh et al., 2014; Sanner et al., 2021); Patch-clamp studies in HEK293T cells showed reduced peak current,slower inactivation and impaired recovery when temperature was increased to 37 degree Celsius, which may be suggestive of a damaging effect; however, further studies are required to fully demonstrate the physiological effect of this variant; This variant is associated with the following publications: (PMID: 24136861, 26427606, 24006052, 22581653, 30203441, 20129283, 30662450, 34348284) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 28, 2023 | This missense change has been observed in individuals with clinical features of Brugada syndrome (PMID: 20129283, 34348284; Invitae). It has also been observed to segregate with disease in related individuals. This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1712 of the SCN5A protein (p.Gly1712Ser). This variant is present in population databases (rs199473298, gnomAD 0.003%). ClinVar contains an entry for this variant (Variation ID: 67958). 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: 34348284). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
SUDDEN INFANT DEATH SYNDROME;C1832680:Dilated cardiomyopathy 1E;C1837845:Sick sinus syndrome 1;C1859062:Long QT syndrome 3;C1879286:Progressive familial heart block, type 1A;C2751898:Ventricular fibrillation, paroxysmal familial, type 1;C3151464:Atrial fibrillation, familial, 10;C4551804:Brugada syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 10, 2022 | - - |
Cardiac arrhythmia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 18, 2023 | This missense variant replaces glycine with serine at codon 1712 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 transmembrane domain (a.a. 1530-1771). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with Brugada syndrome and long QT syndrome (PMID: 32893267). An in-vitro functional study has shown reduced current function and impaired inactivation when compared to wild-type currents (PMID: 34348284). This variant has been reported in three individuals from a family, including the proband affected with ventricular fibrillation, the brother affected with cardiac conduction disease, and the mother affected with Brugada syndrome (PMID: 34348284). This variant has also been reported in an individual suspected of having Brugada syndrome (PMID: 20129283), in an individual affected with hypertrophic cardiomyopathy (PMID: 32746448), in an individual affected with dilated cardiomyopathy (PMID: 29892087) and in a case of sudden unexplained death (PMID: 24136861). This variant has been identified in 1/251432 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. - |
Brugada 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 Brugada syndrome in the following publications (PMID:20129283). 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