3-38551504-C-T

Position:

• chr3-38551504-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000335.5(SCN5A):​c.4865G>A​(p.Arg1622Gln) 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1622L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SCN5A NM_000335.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 7.83

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 19 ACMG points.

• PM1: In a transmembrane_region Helical; Name=S4 of repeat IV (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 chr3-38551504-C-A 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, 0.978
• PP5: Variant 3-38551504-C-T is Pathogenic according to our data. Variant chr3-38551504-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 9376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38551504-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.4868G>A	p.Arg1623Gln	missense_variant	28/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.4865G>A	p.Arg1622Gln	missense_variant	28/28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.4868G>A	p.Arg1623Gln	missense_variant	28/28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.4865G>A	p.Arg1622Gln	missense_variant	28/28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 24, 2019	Published functional studies using whole cell and/or single channel current analysis show that R1623Q causes a significantly slower inactivation rate of the sodium ion channel, and leads to prolonged opening of the sodium ion channel (Makita et al., 1998; Kambouris et al., 1998); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar as pathogenic (ClinVar Variant ID# 9376; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 32383558, 15670972, 25554238, 15184283, 19716085, 12574983, 9506831, 16922724, 24218437, 9495298, 10200053, 19167409, 24136861, 10772658, 20090423) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 25, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SCN5A function (PMID: 9495298, 9506831, 10618304, 10772658, 15621041, 19167409, 20090423). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 9376). This missense change has been observed in individual(s) with long QT syndrome and severe cardiac outcomes (PMID: 10200053, 10508990, 15051636, 15184283, 15670972, 19841300, 19863579, 20129283, 22360817, 24218437, 25904541). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1623 of the SCN5A protein (p.Arg1623Gln). -

Long QT syndrome 3/6, digenic Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2006

- -

Long QT syndrome 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2006

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 26, 2024

The p.R1623Q pathogenic mutation (also known as c.4868G>A), located in coding exon 27 of the SCN5A gene, results from a G to A substitution at nucleotide position 4868. The arginine at codon 1623 is replaced by glutamine, an amino acid with highly similar properties. This mutation has been reported as de novo in cases of long QT syndrome (LQTS) (Yamagishi H et al. Hum Mutat, 1998;11:481; Heron SE et al. Epilepsia, 2010 Feb;51:293-6). This variant has also been reported in LQTS and sudden cardiac death cohorts (Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303; Wattanasirichaigoon D et al. Am J Med Genet, 1999 Oct;86:470-6; Splawski I et al. Circulation, 2000 Sep;102:1178-85; Cuneo BF et al. Circulation, 2013 Nov;128:2183-91; Guo L et al. JAMA Cardiol, 2021 Sep;6:1013-1022). This mutation has also been noted to have an impact on protein function (Makita N et al. FEBS Lett, 1998 Feb;423:5-9; Kambouris NG et al. Circulation, 1998 Feb;97:640-4). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

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:9495298;PMID:9506831;PMID:10973849;PMID:12574983;PMID:15051636;PMID:15184283;PMID:16922724;PMID:19167409;PMID:19716085;PMID:19841300;PMID:20090423;PMID:10772658). 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	0.98
CardioboostCm	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	.;.;.;.;.;D;.;.;.
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	.;D;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	.;.;.;.;.;M;.;.;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.6	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.097	T;T;T;T;T;T;T;T;T
Polyphen		0.99	D;D;.;D;.;P;D;.;.
Vest4		0.71
MutPred		0.92		.;.;Loss of catalytic residue at R1623 (P = 0.0256);.;.;Loss of catalytic residue at R1623 (P = 0.0256);.;.;.;
MVP		1.0
MPC		1.3
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.80
gMVP		0.96

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: rs137854600; hg19: chr3-38592995;