rs199473284
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001099404.2(SCN5A):c.4885C>T(p.Arg1629Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000496 in 1,613,956 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 Pathogenic (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Consequence
SCN5A
NM_001099404.2 stop_gained
NM_001099404.2 stop_gained
Scores
2
4
1
Clinical Significance
Conservation
PhyloP100: 3.94
Genes affected
SCN5A (HGNC:10593): (sodium voltage-gated channel alpha subunit 5) The protein encoded by this gene is an integral membrane protein and tetrodotoxin-resistant voltage-gated sodium channel subunit. This protein is found primarily in cardiac muscle and is responsible for the initial upstroke of the action potential in an electrocardiogram. Defects in this gene have been associated with long QT syndrome type 3 (LQT3), atrial fibrillation, cardiomyopathy, and Brugada syndrome 1, all autosomal dominant cardiac diseases. Alternative splicing results in several transcript variants encoding different isoforms. [provided by RefSeq, May 2022]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 70 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 3-38551487-G-A is Pathogenic according to our data. Variant chr3-38551487-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 264276.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38551487-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SCN5A | NM_001099404.2 | c.4885C>T | p.Arg1629Ter | stop_gained | 28/28 | ENST00000413689.6 | NP_001092874.1 | |
SCN5A | NM_000335.5 | c.4882C>T | p.Arg1628Ter | stop_gained | 28/28 | ENST00000423572.7 | NP_000326.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.4885C>T | p.Arg1629Ter | stop_gained | 28/28 | 5 | NM_001099404.2 | ENSP00000410257 | P4 | |
SCN5A | ENST00000423572.7 | c.4882C>T | p.Arg1628Ter | stop_gained | 28/28 | 1 | NM_000335.5 | ENSP00000398266 | A1 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 152068Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251298Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135818
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GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461770Hom.: 0 Cov.: 35 AF XY: 0.00000413 AC XY: 3AN XY: 727170
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152186Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74398
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 28, 2024 | Identified in patients with known or suspected Brugada syndrome in the published literature (PMID: 30050137, 20129283); Identified in a patient with possible long QT syndrome in the published literature (PMID: 27871843); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect as the sodium current is abolished (PMID: 30050137, 25829473); Nonsense variant predicted to result in protein truncation, as the last 388 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 30050137, 30662450, 30193851, 30203441, 34649698, 33131149, 20129283, 27871843, 25829473) - |
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Jul 04, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Oct 27, 2019 | PVS1_Strong, PM1, PS3_Supporting - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 10, 2023 | This sequence change creates a premature translational stop signal (p.Arg1629*) in the SCN5A gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 388 amino acid(s) of the SCN5A protein. This variant is present in population databases (rs199473284, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with Brugada syndrome (PMID: 20129283, 25829473). ClinVar contains an entry for this variant (Variation ID: 264276). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects SCN5A function (PMID: 25829473). This variant disrupts a region of the SCN5A protein in which other variant(s) (p.Glu1823Hisfs*10) have been determined to be pathogenic (PMID: 17897635, 18361072). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Brugada syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Mar 11, 2023 | - - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 31, 2018 | The p.R1629* pathogenic mutation (also known as c.4885C>T), located in coding exon 27 of the SCN5A gene, results from a C to T substitution at nucleotide position 4885. This changes the amino acid from an arginine to a stop codon within coding exon 27. In a study of Brugada syndrome clinical genetic testing, this alteration was reported in one patient (Kapplinger JD et al. Heart Rhythm. 2010;7(1):33-46). In addition, a young adult with Brugada syndrome was described to be compound heterozygous for this mutation in conjunction with another SCN5A alteration on the opposite chromosome, and induced pluripotent stem cell-derived cardiomyocytes generated from this patient exhibited significantly reduced sodium current. The p.R1629* mutation co-segregated with disease from parent to child, and in vitro functional analyses indicated p.R1629* sodium channels have virtually no activity (Tan BY et al. Europace. 2015:1-8.doi:10.1093/europace/euv058; Ma D et al. Sci Rep. 2018;8:11246).Based on the available evidence, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at