rs199473565

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Moderate

The NM_001099404.2(SCN5A):​c.1066G>T​(p.Asp356Tyr) 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D356N) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

SCN5A
NM_001099404.2 missense

Scores

18
1
1

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.91
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 Pathogenic. Variant got 13 ACMG points.

PM1
In a strand (size 2) in uniprot entity SCN5A_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_001099404.2
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr3-38606743-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 67632.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
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 4.7729 (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, 0.992
PP5
Variant 3-38606743-C-A is Pathogenic according to our data. Variant chr3-38606743-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 637989.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SCN5ANM_001099404.2 linkuse as main transcriptc.1066G>T p.Asp356Tyr missense_variant 9/28 ENST00000413689.6
SCN5ANM_000335.5 linkuse as main transcriptc.1066G>T p.Asp356Tyr missense_variant 9/28 ENST00000423572.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SCN5AENST00000413689.6 linkuse as main transcriptc.1066G>T p.Asp356Tyr missense_variant 9/285 NM_001099404.2 P4
SCN5AENST00000423572.7 linkuse as main transcriptc.1066G>T p.Asp356Tyr missense_variant 9/281 NM_000335.5 A1Q14524-2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Brugada syndrome 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingCenter For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And ColleaguesNov 02, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
CardioboostCm
Pathogenic
0.94
BayesDel_addAF
Pathogenic
0.57
D
BayesDel_noAF
Pathogenic
0.58
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.98
.;.;.;.;.;D;.;.;.
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.90
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
1.0
.;D;D;D;D;D;D;.;D
M_CAP
Pathogenic
0.91
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.4
.;H;.;.;.;H;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D;D
PrimateAI
Pathogenic
0.85
D
PROVEAN
Pathogenic
-8.8
D;D;D;D;D;D;D;D;D
REVEL
Pathogenic
0.98
Sift
Pathogenic
0.0
D;D;D;D;D;D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D;D;D;D;D;D
Polyphen
1.0
D;D;.;D;.;D;D;.;.
Vest4
1.0
MutPred
0.90
Loss of disorder (P = 0.0795);Loss of disorder (P = 0.0795);Loss of disorder (P = 0.0795);Loss of disorder (P = 0.0795);Loss of disorder (P = 0.0795);Loss of disorder (P = 0.0795);Loss of disorder (P = 0.0795);Loss of disorder (P = 0.0795);Loss of disorder (P = 0.0795);
MVP
0.97
MPC
1.3
ClinPred
1.0
D
GERP RS
4.7
Varity_R
0.98
gMVP
1.0

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs199473565; hg19: chr3-38648234; COSMIC: COSV61139761; API