rs1553695282
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The ENST00000423572.7(SCN5A):c.4144C>T(p.Gln1382Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Consequence
SCN5A
ENST00000423572.7 stop_gained
ENST00000423572.7 stop_gained
Scores
2
3
2
Clinical Significance
Conservation
PhyloP100: 1.78
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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 3-38560245-G-A is Pathogenic according to our data. Variant chr3-38560245-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 431948.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38560245-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.4147C>T | p.Gln1383Ter | stop_gained | 23/28 | ENST00000413689.6 | NP_001092874.1 | |
SCN5A | NM_000335.5 | c.4144C>T | p.Gln1382Ter | stop_gained | 23/28 | ENST00000423572.7 | NP_000326.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.4147C>T | p.Gln1383Ter | stop_gained | 23/28 | 5 | NM_001099404.2 | ENSP00000410257 | P4 | |
SCN5A | ENST00000423572.7 | c.4144C>T | p.Gln1382Ter | stop_gained | 23/28 | 1 | NM_000335.5 | ENSP00000398266 | A1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 11, 2016 | The Q1383X variant in the SCN5A gene has been reported in a man diagnosed at age 40 with Brugada syndrome who also harbored a L619F variant in the SCN5A gene that was reported to be pathogenic (Kapplinger et al., 2010). Although it was not reported if these variants were in cis or trans, Kapplinger et al. (2010) found that both the Q1383X and L619F variants were absent in >2600 control alleles. Moreover, the Q1383X likely pathogenic variant is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Other nonsense variants in the SCN5A gene have been reported in HGMD in association with Brugada syndrome (Stenson et al., 2014). Furthermore, the Q1383X variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 22, 2018 | For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in SCN5A are known to be pathogenic (PMID: 20129283, 22789973). This variant has been reported in an individual referred for testing for Brugada syndrome (PMID: 20129283). ClinVar contains an entry for this variant (Variation ID: 431948). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln1383*) in the SCN5A gene. It is expected to result in an absent or disrupted protein product. - |
Brugada syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jul 29, 2024 | This variant changes 1 nucleotide in exon 23 of the SCN5A gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has been reported in individual(s) affected with Brugada syndrome (PMID: 20129283, 32893267). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of SCN5A function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 14, 2024 | The p.Q1383* pathogenic mutation (also known as c.4147C>T), located in coding exon 22 of the SCN5A gene, results from a C to T substitution at nucleotide position 4147. This changes the amino acid from a glutamine to a stop codon within coding exon 22. This alteration was detected in an individual with Brugada syndrome who also harbored an additional SCN5A alteration (Kapplinger JD et al. Heart Rhythm, 2010 Jan;7:33-46). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, 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
Benign
D
MutationTaster
Benign
A;A;A;A;A;A;A;A;A;A
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at