rs199473594

Variant names:

• chr3-38576676-C-T
• rs199473594
• NM_001099404.2:c.3496G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001099404.2(SCN5A):​c.3496G>A​(p.Asp1166Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as not provided (no stars). Synonymous variant affecting the same amino acid position (i.e. D1166D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 2.56
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• Brugada syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Brugada syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Laboratory for Molecular Medicine, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1E

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial long QT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• long QT syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• sick sinus syndrome 1

  Inheritance: AD, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• progressive familial heart block, type 1A

  Inheritance: SD, AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp
• atrial standstill

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial sick sinus syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• paroxysmal familial ventricular fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• progressive familial heart block

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• short QT syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.3496G>A	p.Asp1166Asn	missense_variant	Exon 19 of 28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.3493G>A	p.Asp1165Asn	missense_variant	Exon 19 of 28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.3496G>A	p.Asp1166Asn	missense_variant	Exon 19 of 28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.3493G>A	p.Asp1165Asn	missense_variant	Exon 19 of 28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Congenital long QT syndrome Other:1

-

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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	0.13
CardioboostArm	Benign	0.000031
CardioboostCm	Benign	0.0066
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	.;.;.;.;.;T;.;.;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.82	.;T;T;T;T;T;T;.;T
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.44	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.083	T
MutationAssessor	Benign	1.7	.;.;.;.;.;L;.;.;.
PhyloP100		2.6
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.8	N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.33
Sift	Benign	0.41	T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.30	T;T;T;T;T;T;T;T;T
Polyphen		0.10	B;B;.;B;.;B;P;.;.
Vest4		0.73
MutPred		0.80		Loss of ubiquitination at K1162 (P = 0.0896);.;Loss of ubiquitination at K1162 (P = 0.0896);Loss of ubiquitination at K1162 (P = 0.0896);.;Loss of ubiquitination at K1162 (P = 0.0896);.;.;.;
MVP		0.45
MPC		0.030
ClinPred		0.67	D
GERP RS		4.5
Varity_R		0.18
gMVP		0.72
Mutation Taster		=0/100	disease causing

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

Other links and lift over

dbSNP: rs199473594; hg19: chr3-38618167;