rs199473209

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP2

The NM_000335.5(SCN5A):ā€‹c.3704A>Gā€‹(p.Lys1235Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,732 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K1235N) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 0.0000048 ( 0 hom. )

Consequence

SCN5A
NM_000335.5 missense

Scores

6
6
8

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2O:1

Conservation

PhyloP100: 2.85
Variant links:
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.

PM1
In a topological_domain Extracellular (size 12) in uniprot entity SCN5A_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_000335.5
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr3-38566541-C-A 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.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SCN5ANM_001099404.2 linkuse as main transcriptc.3707A>G p.Lys1236Arg missense_variant 21/28 ENST00000413689.6 NP_001092874.1 Q14524H9KVD2
SCN5ANM_000335.5 linkuse as main transcriptc.3704A>G p.Lys1235Arg missense_variant 21/28 ENST00000423572.7 NP_000326.2 Q14524-2Q86V90

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SCN5AENST00000413689.6 linkuse as main transcriptc.3707A>G p.Lys1236Arg missense_variant 21/285 NM_001099404.2 ENSP00000410257.1 H9KVD2
SCN5AENST00000423572.7 linkuse as main transcriptc.3704A>G p.Lys1235Arg missense_variant 21/281 NM_000335.5 ENSP00000398266.2 Q14524-2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250732
Hom.:
0
AF XY:
0.00000737
AC XY:
1
AN XY:
135676
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000881
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000479
AC:
7
AN:
1461732
Hom.:
0
Cov.:
31
AF XY:
0.00000413
AC XY:
3
AN XY:
727178
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000630
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingClinical Genetics Laboratory, Skane University Hospital LundMay 27, 2022- -
Cardiac arrhythmia Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthSep 28, 2020This missense variant replaces lysine with arginine at codon 1236 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 a study population with families affected with Brugada syndrome (PMID: 21126620). This variant has been identified in 1/250732 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. -
Brugada syndrome Other:1
not provided, no classification providedliterature onlyCardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust-This variant has been reported as associated with Brugada syndrome in the following publications (PMID:21126620). 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.093
CardioboostCm
Benign
0.090
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.15
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.88
.;.;.;.;.;D;.;.;.
Eigen
Benign
0.17
Eigen_PC
Uncertain
0.24
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.91
.;D;D;D;D;D;D;.;D
M_CAP
Pathogenic
0.33
D
MetaRNN
Uncertain
0.46
T;T;T;T;T;T;T;T;T
MetaSVM
Pathogenic
0.93
D
MutationAssessor
Benign
1.4
.;.;.;.;.;L;.;.;.
PrimateAI
Uncertain
0.53
T
PROVEAN
Benign
-2.1
N;N;N;N;N;N;N;N;N
REVEL
Pathogenic
0.76
Sift
Benign
0.23
T;T;T;T;T;T;T;T;T
Sift4G
Benign
0.20
T;T;T;T;T;T;T;T;T
Polyphen
0.75
P;P;.;P;.;P;P;.;.
Vest4
0.39
MutPred
0.52
Loss of methylation at K1236 (P = 0.0096);.;Loss of methylation at K1236 (P = 0.0096);Loss of methylation at K1236 (P = 0.0096);.;Loss of methylation at K1236 (P = 0.0096);.;.;.;
MVP
0.85
MPC
0.42
ClinPred
0.72
D
GERP RS
4.5
Varity_R
0.36
gMVP
0.81

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs199473209; hg19: chr3-38608033; API