rs199473165

chr3-38585951-T-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Moderate

The NM_001099404.2(SCN5A):c.2527A>G(p.Thr843Ala) 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. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. T843T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 8.02

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 Pathogenic. Variant got 11 ACMG points.

• PM1: In a helix (size 19) in uniprot entity SCN5A_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_001099404.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SCN5A
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 3-38585951-T-C is Pathogenic according to our data. Variant chr3-38585951-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 67739.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-38585951-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.2527A>G	p.Thr843Ala	missense_variant	16/28	ENST00000413689.6
SCN5A	NM_000335.5	c.2527A>G	p.Thr843Ala	missense_variant	16/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.2527A>G	p.Thr843Ala	missense_variant	16/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.2527A>G	p.Thr843Ala	missense_variant	16/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 14, 2011

p.Thr843Ala in the SCN5A gene; published, disease-causing mutation (Berge KE et al. 2008) The A>G nucleotide substitution in exon 16 of the SCN5A gene, results in replacement of the normal Threonine codon (ACA) with an Alanine codon (GCA) at amino acid position 843 in the cardiac sodium voltage-gated channel, type V-a. This missense change is denoted Thr843Ala (aka T843A) at the protein level and c.2527 A>G at the cDNA level. The Thr843Ala mutation in the SCN5A gene has been published previously in association with LQTS. Berge et al. (2008) reported Thr843Ala in a single Norwegian individual referred for LQTS testing and did not observe the mutation in 188 Norwegian control alleles (Berge KE et al. 2008). In addition, the Thr843Ala mutation was not detected in 400 alleles from control individuals of Caucasian and African American ancestry tested at GeneDx, indicating it is not a common benign variant in these populations. Thr843Ala results in a non-conservative amino acid substitution of a polar Threonine with a non-polar Alanine at a residue that is highly conserved across species. Additionally, in silico analysis predicts Thr843Ala is probably damaging to the protein structure/function (Adzhubei IA et al. 2010). Furthermore, mutations at surrounding codons (G840R, I839P, S835L, I848F) have been reported in association with LQTS or Brugada syndrome, further supporting the functional significance of this region of the protein. The variant is found in LQT panel(s). -

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:16244680;PMID:18752142). 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	0.96
CardioboostArm	Pathogenic	1.0
CardioboostCm	Uncertain	0.78
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.9	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;D;.;D;D;.;.
Vest4		0.95
MutPred		0.90		Loss of catalytic residue at T843 (P = 0.3906);Loss of catalytic residue at T843 (P = 0.3906);Loss of catalytic residue at T843 (P = 0.3906);Loss of catalytic residue at T843 (P = 0.3906);Loss of catalytic residue at T843 (P = 0.3906);Loss of catalytic residue at T843 (P = 0.3906);Loss of catalytic residue at T843 (P = 0.3906);Loss of catalytic residue at T843 (P = 0.3906);Loss of catalytic residue at T843 (P = 0.3906);
MVP		1.0
MPC		1.1
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.90
gMVP		0.92

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: rs199473165; hg19: chr3-38627442;