rs199473298

Variant names:

• chr3-38551238-C-T
• rs199473298
• NM_001099404.2:c.5134G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PP3_Strong PP5

The NM_001099404.2(SCN5A):​c.5134G>A​(p.Gly1712Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/24 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1712D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:4 O:1
• Conservation: PhyloP100: 7.89
• Publications: 11 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_001099404.2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 3-38551238-C-T is Pathogenic according to our data. Variant chr3-38551238-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 67958.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.5134G>A	p.Gly1712Ser	missense_variant	Exon 28 of 28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.5131G>A	p.Gly1711Ser	missense_variant	Exon 28 of 28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.5134G>A	p.Gly1712Ser	missense_variant	Exon 28 of 28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.5131G>A	p.Gly1711Ser	missense_variant	Exon 28 of 28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251432 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 0.00000821 AC: 12 AN: 1461888 Hom.: 0 Cov.: 35 AF XY: 0.00000688 AC XY: 5 AN XY: 727244

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112006

Other (OTH) AF: 0.0000331 AC: 2 AN: 60396

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:4 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Uncertain:1

Jun 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1712 of the SCN5A protein (p.Gly1712Ser). This variant is present in population databases (rs199473298, gnomAD 0.003%). This missense change has been observed in individuals with clinical features of Brugada syndrome (PMID: 20129283, 34348284; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 67958). 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: 34348284). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SCN5A: PM1, PM2, PM5, PS4:Moderate, PP3, PS3:Supporting -

Jun 14, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; Identified in a patient referred for Brugada syndrome (BrS) genetic testing and in a single family with histories of cardiac arrest, incomplete bundle branch block and amjaline- induced BrS (Kapplinger et al., 2010; Walsh et al., 2014; Sanner et al., 2021); Patch-clamp studies in HEK293T cells showed reduced peak current,slower inactivation and impaired recovery when temperature was increased to 37 degree Celsius, which may be suggestive of a damaging effect; however, further studies are required to fully demonstrate the physiological effect of this variant; This variant is associated with the following publications: (PMID: 24136861, 26427606, 24006052, 22581653, 30203441, 20129283, 30662450, 34348284) -

SUDDEN INFANT DEATH SYNDROME;C1832680:Dilated cardiomyopathy 1E;C1837845:Sick sinus syndrome 1;C1859062:Long QT syndrome 3;C1879286:Progressive familial heart block, type 1A;C2751898:Ventricular fibrillation, paroxysmal familial, type 1;C3151464:Atrial fibrillation, familial, 10;C4551804:Brugada syndrome 1 Pathogenic:1 Uncertain:1

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PP3_Strong+PP2+PS4_Supporting+PP1 -

Mar 10, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiac arrhythmia Uncertain:2

Dec 18, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glycine with serine at codon 1712 of the SCN5A protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. This variant is found within a highly conserved transmembrane domain (a.a. 1530-1771). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with Brugada syndrome and long QT syndrome (PMID: 32893267). An in-vitro functional study has shown reduced current function and impaired inactivation when compared to wild-type currents (PMID: 34348284). This variant has been reported in three individuals from a family, including the proband affected with ventricular fibrillation, the brother affected with cardiac conduction disease, and the mother affected with Brugada syndrome (PMID: 34348284). This variant has also been reported in an individual suspected of having Brugada syndrome (PMID: 20129283), in an individual affected with hypertrophic cardiomyopathy (PMID: 32746448), in an individual affected with dilated cardiomyopathy (PMID: 29892087) and in a case of sudden unexplained death (PMID: 24136861). This variant has been identified in 1/251432 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Dec 02, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glycine with serine at codon 1712 of the SCN5A protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. This variant is found within a highly conserved transmembrane domain (a.a. 1530-1771). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with Brugada syndrome and long QT syndrome (PMID: 32893267). An in-vitro functional study has shown reduced current function and impaired inactivation when compared to wild-type currents (PMID: 34348284). This variant has been reported in three individuals from a family, including the proband affected with ventricular fibrillation, the brother affected with cardiac conduction disease, and the mother affected with Brugada syndrome (PMID: 34348284). This variant has also been reported in an individual suspected of having Brugada syndrome (PMID: 20129283), in an individual affected with hypertrophic cardiomyopathy (PMID: 32746448), in an individual affected with dilated cardiomyopathy (PMID: 29892087) and in a case of sudden unexplained death (PMID: 24136861). This variant has been identified in 1/251432 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Brugada syndrome 1 Pathogenic:1

Oct 23, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PS3_SUP,PM5,PS4_MOD,PP3 -

SCN5A-related disorder Pathogenic:1

Sep 27, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SCN5A c.5134G>A variant is predicted to result in the amino acid substitution p.Gly1712Ser. This variant has been reported in multiple individuals with Brugada Syndrome/Dravet syndrome (Kapplinger et al. 2010. PubMed ID: 20129283; Table S1, Chen et al. 2018. PubMed ID: 30662450; Walsh et al. 2014. PubMed ID: 24136861; Sanner et al. 2021. PubMed ID: 34348284). Functional studies support pathogenicity of this variant (Sanner et al. 2021. PubMed ID: 34348284). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as likely pathogenic. -

Brugada 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 Brugada syndrome in the following publications (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	0.94
CardioboostArm	Pathogenic	1.0
CardioboostCm	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	.;.;.;.;.;D;.;.;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	.;D;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Uncertain	2.1	.;.;.;.;.;M;.;.;.
PhyloP100		7.9
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.5	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;D;.;D;D;.;.
Vest4		0.95
MutPred		0.98		.;.;Loss of stability (P = 0.0846);.;.;Loss of stability (P = 0.0846);.;.;.;
MVP		0.99
MPC		1.4
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.88
gMVP		0.97
Mutation Taster		=0/100	disease causing

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

Other links and lift over

dbSNP: rs199473298; hg19: chr3-38592729; COSMIC: COSV107365927; COSMIC: COSV107365927;