3-38554372-C-T
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Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP2PP3_StrongPP5
The NM_000335.5(SCN5A):c.4717G>A(p.Glu1573Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,738 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).
Frequency
Genomes: not found (cov: 31)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
SCN5A
NM_000335.5 missense
NM_000335.5 missense
Scores
15
4
1
Clinical Significance
Conservation
PhyloP100: 7.86
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 10 ACMG points.
PM1
In a helix (size 27) in uniprot entity SCN5A_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_000335.5
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SCN5A. . Gene score misZ 2.7504 (greater than the threshold 3.09). Trascript score misZ 4.8279 (greater than threshold 3.09). GenCC has associacion of gene with progressive familial heart block, type 1A, Brugada syndrome, familial sick sinus syndrome, short QT syndrome, paroxysmal familial ventricular fibrillation, progressive familial heart block, long QT syndrome 3, familial atrial fibrillation, catecholaminergic polymorphic ventricular tachycardia, dilated cardiomyopathy, dilated cardiomyopathy 1E, arrhythmogenic right ventricular cardiomyopathy, Brugada syndrome 1, atrial standstill, familial isolated dilated cardiomyopathy, familial long QT syndrome, sick sinus syndrome 1.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.993
PP5
Variant 3-38554372-C-T is Pathogenic according to our data. Variant chr3-38554372-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67918.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, not_provided=1, Likely_pathogenic=1}. Variant chr3-38554372-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SCN5A | NM_001099404.2 | c.4720G>A | p.Glu1574Lys | missense_variant | 27/28 | ENST00000413689.6 | NP_001092874.1 | |
SCN5A | NM_000335.5 | c.4717G>A | p.Glu1573Lys | missense_variant | 27/28 | ENST00000423572.7 | NP_000326.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.4720G>A | p.Glu1574Lys | missense_variant | 27/28 | 5 | NM_001099404.2 | ENSP00000410257.1 | ||
SCN5A | ENST00000423572.7 | c.4717G>A | p.Glu1573Lys | missense_variant | 27/28 | 1 | NM_000335.5 | ENSP00000398266.2 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 genomes
Cov.:
31
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461738Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727156
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31
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727156
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GnomAD4 genome Cov.: 31
GnomAD4 genome
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31
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:2Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 21, 2021 | The p.E1574K variant (also known as c.4720G>A), located in coding exon 26 of the SCN5A gene, results from a G to A substitution at nucleotide position 4720. The glutamic acid at codon 1574 is replaced by lysine, an amino acid with similar properties, and is located in the DIV-S2 transmembrane spanning region of the protein. This alteration was detected in an an individual reported to have Brugada syndrome (BrS) with type 1 ECG and inducible ventricular arrhythmia (Zumhagen S et al. Circ Arrhythm Electrophysiol. 2009;2:16-23; Gaborit N et al. Eur Heart J. 2009;30:487-96). This variant was also detected in additional individuals with BrS type 1 ECG, ventricular arrhythmia or syncope, and family history of sudden death in one kindred. The variant was also reportedly detected in several kindred members with spontaneous BrS type1 ECG as well as in some with normal baseline ECGs at the time of study (Ribeiro S et al. Rev Port Cardiol (Engl Ed). 2019 Jul;38(7):503-509). This variant has also been detected in individuals from BrS syndrome cohorts or cohorts referred for BrS genetic testing; however, clinical details were limited and some reports may overlap (Kapplinger JD et al. Heart Rhythm. 2010;7:33-46; Ciconte G et al. Eur Heart J. 2021 03;42(11):1082-1090; Walsh R et al. Genet Med. 2021 01;23(1):47-58). Based on internal structural analysis, this alteration disrupts a residue involved in the gating function of voltage-sensing domains (Seoh SA et al. Neuron. 1996 Jun;16(6):1159-67; Chamberlin A et al. J Mol Biol 2015;427(1):131-45; Ambry internal data). In one in vitro functional study, this variant resulted in reduced peak current density compared to wild type when expressed in the mock-homozygous state; however, the physiological relevance of this finding is unclear (Glazer AM. Am J Hum Genet. 2020 07;107(1):111-123). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 26, 2018 | This sequence change replaces glutamic acid with lysine at codon 1574 of the SCN5A protein (p.Glu1574Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with Brugada syndrome (PMID:  19808440, 20129283). ClinVar contains an entry for this variant (Variation ID: 67918). 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Cardiac arrhythmia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Sep 23, 2024 | - - |
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:19808440;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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
CardioboostCm
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
.;.;.;.;.;D;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
.;D;D;D;D;D;.;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
.;.;.;.;.;H;.;.
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D;D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D;D;D;D
Polyphen
D;D;.;D;.;D;.;.
Vest4
MutPred
0.95
.;.;Gain of methylation at E1574 (P = 0.0115);.;.;Gain of methylation at E1574 (P = 0.0115);.;.;
MVP
MPC
0.92
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
DS_DG_spliceai
Position offset: 3
Find out detailed SpliceAI scores and Pangolin per-transcript scores at