rs137854609

Variant names:

• chr3-38581170-C-A
• rs137854609
• NM_001099404.2:c.2989G>T

Your query was ambiguous. Multiple possible variants found:

• chr3-38581170-C-A
• chr3-38581170-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP5

The NM_001099404.2(SCN5A):​c.2989G>T​(p.Ala997Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000621 in 1,611,146 control chromosomes in the GnomAD database, with no homozygous occurrence. 15/24 in silico tools predict a benign 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. A997T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:3 O:1
• Conservation: PhyloP100: -3.52
• Publications: 25 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 1 ACMG points.

• PP5: Variant 3-38581170-C-A is Pathogenic according to our data. Variant chr3-38581170-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 9388.

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.2989G>T	p.Ala997Ser	missense	Exon 17 of 28	NP_001092874.1
	SCN5A	NM_000335.5	MANE Select	c.2989G>T	p.Ala997Ser	missense	Exon 17 of 28	NP_000326.2
	SCN5A	NM_198056.3		c.2989G>T	p.Ala997Ser	missense	Exon 17 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.2989G>T	p.Ala997Ser	missense	Exon 17 of 28	ENSP00000410257.1
	SCN5A	ENST00000423572.7	TSL:1 MANE Select	c.2989G>T	p.Ala997Ser	missense	Exon 17 of 28	ENSP00000398266.2
	SCN5A	ENST00000333535.9	TSL:1	c.2989G>T	p.Ala997Ser	missense	Exon 17 of 28	ENSP00000328968.4

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152018 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 239824 AF XY: 0.00

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: 0.00000480 AC: 7 AN: 1459128 Hom.: 0 Cov.: 36 AF XY: 0.00000551 AC XY: 4 AN XY: 725728

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44418

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26048

East Asian (EAS) AF: 0.00 AC: 0 AN: 39636

South Asian (SAS) AF: 0.00 AC: 0 AN: 85970

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52838

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1110774

Other (OTH) AF: 0.00 AC: 0 AN: 60220

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152018 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74260

African (AFR) AF: 0.00 AC: 0 AN: 41392

American (AMR) AF: 0.00 AC: 0 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67992

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Aug 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 997 of the SCN5A protein (p.Ala997Ser). This variant is present in population databases (rs137854609, gnomAD 0.0008%). This missense change has been observed in individual(s) with clinical features of SCN5A-related conditions (PMID: 11710892, 18378609, 19716085). ClinVar contains an entry for this variant (Variation ID: 9388). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects SCN5A function (PMID: 11710892). 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.

Sep 19, 2011

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Ala997Ser mutation in the SCN5A gene was first reported by Ackerman et al. in a Caucasian male infant from a cohort of 93 possible Sudden Infant Death Syndrome (SIDS) cases, and was absent from 800 control alleles (Ackerman et al 2001). Ackerman et al. also reported that Ala997Ser showed an altered pattern of sodium current. Ala997Ser was also reported by Darbar et al. in a single patient with atrial fibrillation, but was also present in one out of 720 control alleles (Darbar et al 2008). Finally, Kapplinger et al. reported Ala997Ser in a single individual referred for LQTS testing, and was absent from at least 2,600 control alleles from individuals of various ethnic backgrounds (Kapplinger et al 2009). Located in the highly conserved DII-DIII intracellular domain linker region of SCN5A, Ala997Ser represents a non-conservative amino acid substitution of a non-polar Alanine residue with a polar Serine residue. Furthermore, a mutation in the same codon (Ala997Thr) has been reported in association with Brugada syndrome, further supporting the functional significance of this region of the protein. The variant is found in LQT panel(s).

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 alanine with serine at codon 997 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies suggest a possible impact of this variant on sodium channel activity, however the clinical relevance of this observation is not known (PMID: 11710892). This variant has been reported in 1 individual with suspected long QT syndrome (PMID: 19716085), in 2 individuals with sudden death (PMID: 11710892, 29544605), and in 1 individual with atrial fibrillation (PMID: 18378609). This variant has been identified in 1/271150 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.

Apr 27, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces alanine with serine at codon 997 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies suggest a possible impact of this variant on sodium channel activity, however the clinical relevance of this observation is not known (PMID: 11710892). This variant has been reported in 1 individual with suspected long QT syndrome (PMID: 19716085), in 2 individuals with sudden death (PMID: 11710892, 29544605), and in 1 individual with atrial fibrillation (PMID: 18378609). This variant has been identified in 1/271150 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.

Dilated cardiomyopathy 1E;C1859062:Long QT syndrome 3;C3151464:Atrial fibrillation, familial, 10;C4551804:Brugada syndrome 1 Pathogenic:1

Dec 23, 2024

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SCN5A c.2989G>T (p.Ala997Ser) variant has been reported in at least three individuals affected with sudden infant death syndrome, atrial fibrillation, and long QT syndrome (Ackerman MJ et al., PMID: 11710892; Darbar D et al., PMID: 18378609; Kapplinger JD et al., PMID: 19716085). This variant is only observed on 1/271,150 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. Functional studies show that this variant results in slower decay with a 2-3 fold increase in late sodium current, indicating that this variant impacts protein function (Ackerman MJ et al., PMID: 11710892). Computational predictors are uncertain as to the impact of this variant on SCN5A function. Other variants in the same codon, c.2990C>A (p.Ala997Asp) and c.2989G>A (p.Ala997Thr), have been reported in individuals with sudden death syndromes (Wang D et al., PMID: 24631775; Ciconte G et al., PMID: 33221895) and are considered variants of uncertain significance; ClinVar Variation IDs: 67771, 165149). This variant has been reported in the ClinVar database as a germline pathogenic or likely pathogenic variant by three submitters and a variant of uncertain significance by three submitters. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as likely pathogenic.

SCN5A-related disorder Pathogenic:1

Sep 16, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SCN5A c.2989G>T variant is predicted to result in the amino acid substitution p.Ala997Ser. This variant has been reported in multiple cohorts of sudden infant death syndrome and in a patient with a long QT syndrome phenotype (Ackerman et al. 2001. PubMed ID: 11710892; Kapplinger et al. 2009. PubMed ID: 19716085; Tester et al. 2018. PubMed ID: 29544605). This variant is reported in 0.00081% of alleles in individuals of European (non-Finnish) descent in gnomAD. An in vitro experimental study suggests this variant may disrupt sodium currents (Ackerman et al. 2001. PubMed ID: 11710892). Alternate missense substitutions affecting the same amino acid (p.Ala997Asp and p.Ala997Thr) have been reported in multiple cohorts of sudden death syndromes (Wang et al. 2014. PubMed ID: 24631775; Ciconte et al. 2021. PubMed ID: 33221895). Taken together, the c.2989G>T (p.Ala997Ser) variant is interpreted as likely pathogenic.

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

Feb 15, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Long QT syndrome 3 Pathogenic:1

Nov 14, 2001

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:11710892;PMID:19716085). 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	Benign	0.071
CardioboostArm	Benign	0.0000065
CardioboostCm	Benign	0.0017
BayesDel_addAF	Uncertain	0.023	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	0.0030
DANN	Benign	0.34
DEOGEN2	Benign	0.38	T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.089	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.080	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.0	N
PhyloP100		-3.5
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.42	N
REVEL	Uncertain	0.49
Sift	Benign	0.57	T
Sift4G	Benign	0.83	T
Polyphen		0.0010	B
Vest4		0.68
MutPred		0.78		Gain of glycosylation at A997 (P = 0.038)
MVP		0.99
MPC		0.028
ClinPred		0.037	T
GERP RS		-11
Varity_R		0.040
gMVP		0.44
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs137854609; hg19: chr3-38622661; COSMIC: COSV61119231;