chr3-38551486-C-T
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong
The NM_001099404.2(SCN5A):c.4886G>A(p.Arg1629Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,840 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1629G) 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.4886G>A | p.Arg1629Gln | missense_variant | 28/28 | ENST00000413689.6 | |
SCN5A | NM_000335.5 | c.4883G>A | p.Arg1628Gln | missense_variant | 28/28 | ENST00000423572.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.4886G>A | p.Arg1629Gln | missense_variant | 28/28 | 5 | NM_001099404.2 | P4 | |
SCN5A | ENST00000423572.7 | c.4883G>A | p.Arg1628Gln | missense_variant | 28/28 | 1 | NM_000335.5 | A1 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152066Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251304Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135826
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461774Hom.: 0 Cov.: 35 AF XY: 0.00000413 AC XY: 3AN XY: 727174
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152066Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74292
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 03, 2019 | Published functional studies demonstrate loss-of-function of cardiac sodium channel by shifting voltage dependence of inactivation, enhanced intermediate inactivation, and prolonged recovery time from inactivation (Zeng et al., 2013).; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID# 67937; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 20129283, 21273195, 24167619, 22373669, 26031372, 30662450, 22581653, 31447099, 33131149) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 10, 2022 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1629 of the SCN5A protein (p.Arg1629Gln). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SCN5A function (PMID: 24167619). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 67937). This missense change has been observed in individuals with Brugada syndrome (PMID: 20129283, 21273195, 24167619, 33164571). This variant is present in population databases (rs199473623, gnomAD 0.006%). - |
Long QT syndrome 3 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Nov 03, 2017 | A heterozygous likely pathogenic variant in the SCN5A gene was detected in this individuals. This variant has been previously described as disease-causing in Brugada syndrome (MIM 601144; PMID: 20129283, 24167619), an autosomal dominant cardiac conduction defect disorder. In addition, functional studies have indicated that the p.R1629Q change alters sodium channel function (PMID: 20129283). Therefore, we consider this variant to be likely pathogenic. - |
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