rs199473057

Positions:

• chr3-38630360-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_001099404.2(SCN5A):​c.343A>G​(p.Ser115Gly) variant causes a missense change. 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 not provided (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 6.27

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 130) in uniprot entity SCN5A_HUMAN there are 19 pathogenic changes around while only 2 benign (90%) in NM_001099404.2
• 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 4.7729 (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, 0.927

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.343A>G	p.Ser115Gly	missense_variant	3/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.343A>G	p.Ser115Gly	missense_variant	3/28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.343A>G	p.Ser115Gly	missense_variant	3/28	5	NM_001099404.2	ENSP00000410257	P4
SCN5A	ENST00000423572.7	c.343A>G	p.Ser115Gly	missense_variant	3/28	1	NM_000335.5	ENSP00000398266	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

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:19716085). 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	0.16
CardioboostCm	Benign	0.076
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	.;.;.;.;.;D;.;.;.;T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.83	.;T;T;T;T;T;T;.;T;T
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.1	.;L;.;.;.;L;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.5	D;D;D;D;D;D;D;D;D;.
REVEL	Pathogenic	0.83
Sift	Benign	0.10	T;T;T;T;D;T;T;D;D;.
Sift4G	Benign	0.28	T;T;T;T;T;T;T;T;T;D
Polyphen		0.69	P;D;.;P;.;P;D;.;.;.
Vest4		0.90
MutPred		0.83		Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);
MVP		0.93
MPC		1.1
ClinPred		0.98	D
GERP RS		5.1
Varity_R		0.50
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

Other links and lift over

dbSNP: rs199473057; hg19: chr3-38671851;