Genetic Variant SCN5A:p.Arg1623Gln (chr3-38551504-C-T) – ACMG Classification: Pathogenic (18 pts)

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_001099404.2(SCN5A):c.4868G>A(p.Arg1623Gln) 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. 15/24 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. R1623L) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 31)

Consequence

SCN5A
NM_001099404.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5O:1

Conservation

PhyloP100: 7.83

Publications

65 publications found

Variant links:

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

SCN5A links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_001099404.2

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 ClinVar as Likely_pathogenic. ClinVar VariationId is 67933.Status of the report is criteria_provided_single_submitter, 1 stars.

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 VariationId is 9376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001099404.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SCN5A	NM_001099404.2	MANE Plus Clinical	c.4868G>A	p.Arg1623Gln	missense	Exon 28 of 28	NP_001092874.1
SCN5A	NM_000335.5	MANE Select	c.4865G>A	p.Arg1622Gln	missense	Exon 28 of 28	NP_000326.2
SCN5A	NM_198056.3		c.4868G>A	p.Arg1623Gln	missense	Exon 28 of 28	NP_932173.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SCN5A	ENST00000413689.6	TSL:5 MANE Plus Clinical	c.4868G>A	p.Arg1623Gln	missense	Exon 28 of 28	ENSP00000410257.1
SCN5A	ENST00000423572.7	TSL:1 MANE Select	c.4865G>A	p.Arg1622Gln	missense	Exon 28 of 28	ENSP00000398266.2
SCN5A	ENST00000333535.9	TSL:1	c.4868G>A	p.Arg1623Gln	missense	Exon 28 of 28	ENSP00000328968.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Sep 19, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 (PMID: 9506831, 9495298); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20090423, 10772658, 24136861, 19167409, 9495298, 24218437, 16922724, 19716085, 15184283, 25554238, 15670972, 30203441, 10618304, 15621041, 32383558, 34076677, 39602950, 9506831, 10200053, 12574983)

Jun 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). This variant is not present in population databases (gnomAD no frequency). 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. ClinVar contains an entry for this variant (Variation ID: 9376). 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. Experimental studies have shown that this missense change affects SCN5A function (PMID: 9495298, 9506831, 10618304, 10772658, 15621041, 19167409, 20090423). For these reasons, this variant has been classified as Pathogenic.

Long QT syndrome 3/6, digenic

Pathogenic:1

Sep 01, 2006

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Cardiovascular phenotype

Pathogenic:1

Aug 26, 2024

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Long QT syndrome 3

Pathogenic:1

Sep 01, 2006

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

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: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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

CardioboostArm

Pathogenic

1.0

CardioboostCm

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.95

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.86

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.4

PhyloP100

7.8

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-3.6

REVEL

Pathogenic

0.95

Sift

Uncertain

0.0010

Sift4G

Benign

0.097

Polyphen

0.99

Vest4

0.71

MutPred

0.92

Loss of catalytic residue at R1623 (P = 0.0256)

MVP

1.0

MPC

1.3

ClinPred

0.99

GERP RS

4.5

Varity_R

0.80

gMVP

0.96

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over