rs201276017
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PM5PP2PP3_Moderate
The NM_000335.5(SCN5A):c.1051G>A(p.Gly351Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000744 in 1,613,870 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G351D) has been classified as Pathogenic.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000075 ( 0 hom. )
Consequence
SCN5A
NM_000335.5 missense
NM_000335.5 missense
Scores
12
6
2
Clinical Significance
Conservation
PhyloP100: 6.17
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 Likely_pathogenic. Variant got 7 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr3-38606757-C-T is described in Lovd as [Pathogenic].
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, 0.934
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| SCN5A | NM_001099404.2 | c.1051G>A | p.Gly351Ser | missense_variant | 9/28 | ENST00000413689.6 | NP_001092874.1 | |
| SCN5A | NM_000335.5 | c.1051G>A | p.Gly351Ser | missense_variant | 9/28 | ENST00000423572.7 | NP_000326.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| SCN5A | ENST00000413689.6 | c.1051G>A | p.Gly351Ser | missense_variant | 9/28 | 5 | NM_001099404.2 | ENSP00000410257.1 | ||
| SCN5A | ENST00000423572.7 | c.1051G>A | p.Gly351Ser | missense_variant | 9/28 | 1 | NM_000335.5 | ENSP00000398266.2 |
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152210Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000120 AC: 3AN: 249028Hom.: 0 AF XY: 0.00000740 AC XY: 1AN XY: 135104
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GnomAD4 exome AF: 0.00000753 AC: 11AN: 1461542Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727052
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GnomAD4 genome 0.00000656 AC: 1AN: 152328Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74490
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Brugada syndrome 1 Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Sep 01, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Dec 18, 2024 | - - |
Cardiac arrhythmia Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | This missense variant replaces glycine with serine at codon 351 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with juvenile myoclonic epilepsy and long QT syndrome (Ho 2016). This variant has been identified in 3/249028 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 10, 2023 | This missense variant replaces glycine with serine at codon 351 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with juvenile myoclonic epilepsy and long QT syndrome (Ho 2016). This variant has been identified in 3/249028 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Ventricular fibrillation, paroxysmal familial, type 1 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Sep 01, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Dilated cardiomyopathy 1E Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Sep 01, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
SUDDEN INFANT DEATH SYNDROME;C1832680:Dilated cardiomyopathy 1E;C1837845:Sick sinus syndrome 1;C1859062:Long QT syndrome 3;C1879286:Progressive familial heart block, type 1A;C2751898:Ventricular fibrillation, paroxysmal familial, type 1;C3151464:Atrial fibrillation, familial, 10;C4551804:Brugada syndrome 1 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 07, 2021 | - - |
Sick sinus syndrome 1 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Sep 01, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Brugada syndrome Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 27, 2021 | This sequence change replaces glycine with serine at codon 351 of the SCN5A protein (p.Gly351Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs201276017, ExAC 0.002%). This variant has not been reported in the literature in individuals affected with SCN5A-related conditions. 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. 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. - |
Progressive familial heart block, type 1A Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Sep 01, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Long QT syndrome 3 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Sep 01, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Cardiovascular phenotype Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 05, 2023 | The p.G351S variant (also known as c.1051G>A), located in coding exon 8 of the SCN5A gene, results from a G to A substitution at nucleotide position 1051. The glycine at codon 351 is replaced by serine, an amino acid with similar properties, and is located in the transmembrane-spanning DI-S5/S6 domain. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
CardioboostCm
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
.;.;.;.;.;D;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
.;D;D;D;D;D;D;.;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
.;M;.;.;.;M;.;.;.
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D;D;D;D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D;D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D;D;D;D;D
Polyphen
D;D;.;D;.;D;D;.;.
Vest4
MVP
MPC
1.1
ClinPred
D
GERP RS
Varity_R
gMVP
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