3-38597737-C-T

Variant names:

• chr3-38597737-C-T
• rs199473153
• NM_001099404.2:c.2254G>A

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS1_Very_Strong PP3_Strong PP5_Very_Strong

The NM_001099404.2(SCN5A):​c.2254G>A​(p.Gly752Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000482 in 1,451,322 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 16/26 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 7.82
• Publications: 18 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: Pathogenic. The variant received 20 ACMG points.

• PS1: Transcript NM_001099404.2 (SCN5A) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 3-38597737-C-T is Pathogenic according to our data. Variant chr3-38597737-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 67723.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN5A	NM_001099404.2	MANE Plus Clinical	c.2254G>A	p.Gly752Arg	missense	Exon 14 of 28	NP_001092874.1
	SCN5A	NM_000335.5	MANE Select	c.2254G>A	p.Gly752Arg	missense	Exon 14 of 28	NP_000326.2
	SCN5A	NM_198056.3		c.2254G>A	p.Gly752Arg	missense	Exon 14 of 28	NP_932173.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN5A	ENST00000413689.6	TSL:5 MANE Plus Clinical	c.2254G>A	p.Gly752Arg	missense	Exon 14 of 28	ENSP00000410257.1
	SCN5A	ENST00000423572.7	TSL:1 MANE Select	c.2254G>A	p.Gly752Arg	missense	Exon 14 of 28	ENSP00000398266.2
	SCN5A	ENST00000333535.9	TSL:1	c.2254G>A	p.Gly752Arg	missense	Exon 14 of 28	ENSP00000328968.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000403 AC: 1 AN: 247910 AF XY: 0.00000744

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000482 AC: 7 AN: 1451322 Hom.: 0 Cov.: 31 AF XY: 0.00000417 AC XY: 3 AN XY: 719776

African (AFR) AF: 0.00 AC: 0 AN: 33304

American (AMR) AF: 0.00 AC: 0 AN: 44546

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25982

East Asian (EAS) AF: 0.00 AC: 0 AN: 39454

South Asian (SAS) AF: 0.00 AC: 0 AN: 85820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53284

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.00000634 AC: 7 AN: 1103328

Other (OTH) AF: 0.00 AC: 0 AN: 59864

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000367 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Jun 26, 2024

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 752 of the SCN5A protein (p.Gly752Arg). This variant is present in population databases (rs199473153, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal dominant dilated cardiomyopathy and Brugada syndrome (PMID: 12693506, 20022821, 20129283, 25904541). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 67723). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 32533946) did not meet the statistical confidence thresholds required to predict the impact of this variant on SCN5A function. Experimental studies have shown that this missense change affects SCN5A function (PMID: 12693506, 20022821, 26283144). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.

Nov 22, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Published functional studies demonstrate that G752R results in a loss of function of the sodium channel (Potet et al., 2003; Hoogendijk et al., 2010; Varga et al., 2015).; In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 19251209, 26283144, 18849657, 16627450, 30193851, 31729605, 12693506, 26724572, 20129283, 23874304, 25904541, 24365614, 12106943, 25650408, 20022821, 20031634, 30662450, 30919684, 32048431, 31737537, 31589614, 32880476, 33087929, 33131149)

Brugada syndrome Pathogenic:1 Other:1

Apr 14, 2015

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The SCN5A Gly752Arg variant has been identified in several unrelated individuals with Brugada syndrome (Smits JP, et al., 2002, Meregalli PG, et al., 2009; Kapplinger JD, et al., 2010; Le Scouarnec S, et al., 2015) and was found to be absent in >1300 controls (Kapplinger, JD et al., 2010). The variant has also been reported to segregate with disease in families with Brugada syndrome (Potet F, et al., 2003; Probst V et al., 2009) with functional studies showing deleterious effects on mutant sodium channels (Potet F, et al., 2003). We identified SCN5A Gly752Arg in an Asian proband with Brugada Syndome. The proband had a cardiac arrest whilst febrile aged 2yrs and has a family history of SCD. The SCN5A Gly752Arg variant is found at a low frequency in the 1000 genomes project (MAF= 0.0004; http://www.1000genomes.org/) and is absent from the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). Computational tools SIFT, MutationTaster, and PolyPhen-2 predict this variant to have a deleterious effect. Based on the current literature, rarity in general populations and in silico tool predictions we have evaluated this variant as "likely pathogenic".

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 Brugada syndrome in the following publications (PMID:12106943;PMID:12693506;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.

Cardiovascular phenotype Pathogenic:1

Sep 04, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G752R pathogenic mutation (also known as c.2254G>A), located in coding exon 13 of the SCN5A gene, results from a G to A substitution at nucleotide position 2254. The glycine at codon 752 is replaced by arginine, an amino acid with dissimilar properties. The p.G752R variant, caused by a different nucleotide change (c.2254G>C), was shown to have strong segregation with disease in families with Brugada syndrome demonstrating varying phenotypes (Potet F et al. J Cardiovasc Electrophysiol. 2003;14(2):200-3; Probst et al. Circ Cardiovasc Genet. 2009 Dec;2(6):552-7). The c.2254G>C variant was also seen in a 3-year-old male with Brugada syndrome and atrial flutter that was induced by febrile episodes (Hassink RJ et al. Int J Cardiol. 2014;171(2):e31-4). One study demonstrated that ST-segment elevation coincided with local disappearance of initial activation in the explanted heart of a patient with this alteration (Hoogendijk MG et al. Heart Rhythm. 2010;7(2):238-48). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostArm	Pathogenic	1.0
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		7.8
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.7	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.99
MutPred		0.91		Loss of helix (P = 0.079)
MVP		0.97
MPC		1.2
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.98
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.46		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.46		Position offset: 4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs199473153; hg19: chr3-38639228; COSMIC: COSV61125197;