rs199473253
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PP2PP3_StrongPP5_Moderate
The NM_001099404.2(SCN5A):c.4373C>A(p.Ser1458Tyr) variant causes a missense change involving the alteration of a 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 Pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Consequence
SCN5A
NM_001099404.2 missense
NM_001099404.2 missense
Scores
14
3
1
Clinical Significance
Conservation
PhyloP100: 10.0
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 11 ACMG points.
PM1
?
In a transmembrane_region Helical; Name=S6 of repeat III (size 21) in uniprot entity SCN5A_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) in NM_001099404.2
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, SCN5A
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.984
PP5
?
Variant 3-38556505-G-T is Pathogenic according to our data. Variant chr3-38556505-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 67887.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-38556505-G-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN5A | NM_001099404.2 | c.4373C>A | p.Ser1458Tyr | missense_variant | 25/28 | ENST00000413689.6 | |
SCN5A | NM_000335.5 | c.4370C>A | p.Ser1457Tyr | missense_variant | 25/28 | ENST00000423572.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.4373C>A | p.Ser1458Tyr | missense_variant | 25/28 | 5 | NM_001099404.2 | P4 | |
SCN5A | ENST00000423572.7 | c.4370C>A | p.Ser1457Tyr | missense_variant | 25/28 | 1 | NM_000335.5 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 35
GnomAD4 exome
Cov.:
35
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1Other:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 19, 2012 | The Ser1458Tyr mutation in the SCN5A gene has been reported previously in one individual with LQTS, and this mutation was absent from 1,688 control alleles (Tester D et al., 2005). The NHLBI ESP Exome Variant Server reports Ser1458Tyr was not observed in approximately 5,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Ser1458Tyr results in a conservative substitution of one neutral, polar amino acid for another at a residue that is conserved across species. In silico analysis predicts Ser1458Tyr is probably damaging to the protein structure/function. In addition, mutations in nearby codons (Val1451Asp, Asn1463Tyr) have also been reported in association with familial arrhythmia, supporting the functional importance of this region of the protein. In summary, Ser1458Tyr in the SCN5A gene is interpreted as a disease-causing mutation. The variant is found in LQT panel(s). - |
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:15840476;PMID:19841300). 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
CardioboostArm
Uncertain
CardioboostCm
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D;D;D;D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D;D;D;D;D;D
Sift4G
Pathogenic
D;D;D;D;D;D;D;D;D
Polyphen
D;B;.;D;.;P;D;.;.
Vest4
MutPred
0.89
.;.;Loss of helix (P = 0.1299);.;.;Loss of helix (P = 0.1299);.;.;.;
MVP
MPC
1.6
ClinPred
D
GERP RS
Varity_R
gMVP
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