3-38557236-T-C

Position:

• chr3-38557236-T-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Strong

The NM_000335.5(SCN5A):​c.4291A>G​(p.Arg1431Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1431S) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SCN5A NM_000335.5 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 0.427

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]

SCN5A (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a topological_domain Extracellular (size 16) in uniprot entity SCN5A_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) 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 chr3-38557234-C-G 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, 0.983

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.4294A>G	p.Arg1432Gly	missense_variant	24/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.4291A>G	p.Arg1431Gly	missense_variant	24/28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.4294A>G	p.Arg1432Gly	missense_variant	24/28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.4291A>G	p.Arg1431Gly	missense_variant	24/28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

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:10727653;PMID:20129283;PMID:11420310). 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	Pathogenic	0.95
CardioboostCm	Uncertain	0.63
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.44
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	.;.;.;D;.;.;.
Eigen	Benign	0.11
Eigen_PC	Benign	0.089
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;.;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	.;.;.;M;.;.;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-5.6	D;D;D;D;D;D;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.023	D;D;D;D;D;D;D
Sift4G	Uncertain	0.019	D;D;D;D;D;D;D
Polyphen		0.050	B;.;.;P;D;.;.
Vest4		0.96
MutPred		0.86		.;Gain of glycosylation at S1431 (P = 0.1018);.;Gain of glycosylation at S1431 (P = 0.1018);.;.;.;
MVP		0.97
MPC		1.6
ClinPred		0.97	D
GERP RS		2.9
Varity_R		0.69
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs199473245; hg19: chr3-38598727;