rs199473628

chr3-38551231-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.5141A>G(p.Asp1714Gly) 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. 13/23 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. D1714N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 8.01

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 intramembrane_region Pore-forming (size 22) in uniprot entity SCN5A_HUMAN there are 10 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, 0.983
• PP5: Variant 3-38551231-T-C is Pathogenic according to our data. Variant chr3-38551231-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 67959.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-38551231-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.5141A>G	p.Asp1714Gly	missense_variant	28/28	ENST00000413689.6
SCN5A	NM_000335.5	c.5138A>G	p.Asp1713Gly	missense_variant	28/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.5141A>G	p.Asp1714Gly	missense_variant	28/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.5138A>G	p.Asp1713Gly	missense_variant	28/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 10, 2019

Identified in individuals with Brugada syndrome in published literature (Kapplinger et al., 2011; Amin et al., 2011; Kapplinger et al., 2015); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Published functional studies demonstrate reduction in the sodium channel current density (Amin et al., 2005; Meregalli et al., 2009).; This variant is associated with the following publications: (PMID: 19251209, 19606473, 21273195, 16266370, 25904541, 22373669, 20129283, 22581653, 28150151, 30728299, 30662450, 33131149) -

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:16266370;PMID:19251209;PMID:20129283). 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	0.97
CardioboostArm	Pathogenic	1.0
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
Cadd	Pathogenic	26
Dann	Uncertain	1.0
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-6.0	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0020	D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;D;.;D;D;.;.
Vest4		0.94
MutPred		0.84		.;.;Gain of catalytic residue at G1712 (P = 0.0769);.;.;Gain of catalytic residue at G1712 (P = 0.0769);.;.;.;
MVP		0.98
MPC		1.6
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.94
gMVP		0.99

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: rs199473628; hg19: chr3-38592722;