NM_001099404.2:c.892G>A

Variant names:

• chr3-38609776-C-T
• rs137854608
• NM_001099404.2:c.892G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PP3_Strong

The NM_001099404.2(SCN5A):​c.892G>A​(p.Gly298Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000415 in 1,612,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G298D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000042 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:16 O:1
• Conservation: PhyloP100: 1.51
• Publications: 27 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: Uncertain_significance. The variant received 4 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.892G>A	p.Gly298Ser	missense_variant	Exon 7 of 28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.892G>A	p.Gly298Ser	missense_variant	Exon 7 of 28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.892G>A	p.Gly298Ser	missense_variant	Exon 7 of 28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.892G>A	p.Gly298Ser	missense_variant	Exon 7 of 28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152250 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000241 AC: 6 AN: 248846 AF XY: 0.0000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000888

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000425 AC: 62 AN: 1460366 Hom.: 0 Cov.: 31 AF XY: 0.0000358 AC XY: 26 AN XY: 726248

African (AFR) AF: 0.0000299 AC: 1 AN: 33450

American (AMR) AF: 0.000201 AC: 9 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.0000376 AC: 2 AN: 53170

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000441 AC: 49 AN: 1110926

Other (OTH) AF: 0.00 AC: 0 AN: 60308

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152250 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74384

African (AFR) AF: 0.0000241 AC: 1 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000290 Hom.: 0

Bravo AF: 0.0000453

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:16 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:4

Nov 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

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 298 of the SCN5A protein (p.Gly298Ser). This variant is present in population databases (rs137854608, gnomAD 0.01%). This missense change has been observed in individual(s) with SCN5A-related conditions (PMID: 11804990, 19056759, 31983221, 35352813, 37652022). ClinVar contains an entry for this variant (Variation ID: 9387). 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 tolerated. Experimental studies have shown that this missense change affects SCN5A function (PMID: 11804990, 19056759). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Mar 20, 2020

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 07, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in a patient with second-degree heart block diagnosed in childood that progressed to third-degree AV block (Wang et al., 2002); Identified in a patient with DCM in published literature (Mazzarotto et al., 2020); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies suggest a damaging effect (Wang et al., 2002); however, it is unclear whether these findings recapitulate in vivo conditions; This variant is associated with the following publications: (PMID: 25871451, 17854786, 17111025, 20176021, 25898860, 26401487, 22581653, 23105938, 22323988, 16540748, 19027780, 17504259, 31983221, 11804990, 24535448, 19056759) -

Apr 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SCN5A: PM2, PS4:Moderate, PS3:Supporting -

Progressive familial heart block, type 1A Pathogenic:1 Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Jan 22, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Cardiac arrhythmia Uncertain:2

Mar 26, 2024

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 298 of the SCN5A protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. Functional studies have shown that this variant decreases sodium channel current density and activation kinetics (PMID: 11804990, 19056759). However, clinical relevance of this observation is not clear. This variant has been reported in two individuals affected with atrioventricular conduction block (PMID: 11804990, 37351150); one of these individuals also carried another pathogenic variant in the same gene (PMID: 37351150). This variant has also been reported in one individual affected with irritable bowel syndrome (PMID: 19056759). This variant has also been identified in 7/280252 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. -

Sep 23, 2024

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 298 of the SCN5A protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. Functional studies have shown that this variant decreases sodium channel current density and activation kinetics (PMID: 11804990, 19056759). However, clinical relevance of this observation is not clear. This variant has been reported in two individuals affected with atrioventricular conduction block (PMID: 11804990, 37351150); one of these individuals also carried another pathogenic variant in the same gene (PMID: 37351150). This variant has also been reported in one individual affected with irritable bowel syndrome (PMID: 19056759). This variant has also been identified in 7/280252 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. -

not specified Uncertain:1

Dec 29, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Gly298Ser variant in SCN5A has been reported in 1 Mexican individual with atrioventricular conduction block (Wang 2002), and has been identified by our la b in 1 Indian child with DCM. This variant has been identified in 2/11578 Latino chromosomes and in 1/8724 East Asian chromosomes by the Exome Aggregation Conso rtium (ExAC, http://exac.broadinstitute.org; dbSNP rs137854608). In vitro functi onal studies provide some evidence that the p.Gly298Ser variant may impact prote in function (Wang 2002, Saito 2009). However, these types of assays may not accu rately represent biological function. Additional computational prediction tools and conservation analysis suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In s ummary, the clinical significance of the p.Gly298Ser variant is uncertain. -

Brugada syndrome 1 Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Ventricular fibrillation, paroxysmal familial, type 1 Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Dilated cardiomyopathy 1E Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

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 Uncertain:1

Feb 07, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary dilated cardiomyopathy;C0018991:Hemiplegia;C0149931:Migraine Uncertain:1

Nov 24, 2014

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sick sinus syndrome 1 Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Long QT syndrome 3 Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Cardiovascular phenotype Uncertain:1

Aug 16, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.892G>A (p.G298S) alteration is located in exon 7 (coding exon 6) of the SCN5A gene. This alteration results from a G to A substitution at nucleotide position 892, causing the glycine (G) at amino acid position 298 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Atrioventricular block 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 Atrioventricular conduction block in the following publications (PMID:11804990;PMID:19056759). 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	Benign	0.086
CardioboostArm	Benign	0.00049
CardioboostCm	Benign	0.0044
BayesDel_addAF	Uncertain	0.070	D
BayesDel_noAF	Uncertain	0.090
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.70	.;.;.;.;.;D;.;.;.
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.82	.;T;T;T;T;T;T;.;T
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.38	D
MutationAssessor	Benign	0.37	.;N;.;.;.;N;.;.;.
PhyloP100		1.5
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.47	N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.55
Sift	Benign	0.14	T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.75	T;T;T;T;T;T;T;T;T
Polyphen		0.90	P;D;.;P;.;P;D;.;.
Vest4		0.79
MutPred		0.82		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.95
MPC		0.66
ClinPred		0.049	T
GERP RS		4.0
Varity_R		0.035
gMVP		0.92
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: rs137854608; hg19: chr3-38651267; COSMIC: COSV61138770; COSMIC: COSV61138770;