rs137854609

chr3-38581170-C-Achr3-38581170-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP2 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. 14/22 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. A997D) 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:4 U:3 O:1
• Conservation: PhyloP100: -3.52

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-38581170-C-T is described in Lovd as [Pathogenic].
• PP2: Missense variant where missense usually causes diseases, SCN5A
• 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 id is 9388.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=1, Pathogenic=1, Uncertain_significance=3, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.2989G>T	p.Ala997Ser	missense_variant	17/28	ENST00000413689.6
SCN5A	NM_000335.5	c.2989G>T	p.Ala997Ser	missense_variant	17/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.2989G>T	p.Ala997Ser	missense_variant	17/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.2989G>T	p.Ala997Ser	missense_variant	17/28	1	NM_000335.5	A1

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

GnomAD4 exome AF: 0.00000480 AC: 7 AN: 1459128 Hom.: 0 Cov.: 36 AF XY: 0.00000551 AC XY: 4 AN XY: 725728

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.00

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

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000227

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2024	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). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". 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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 19, 2011	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

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 27, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 18, 2023	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. -

SCN5A-related condition Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 07, 2022

The SCN5A c.2989G>T variant is predicted to result in the amino acid substitution p.Ala997Ser. This variant was reported as pathogenic in a cohort of sudden infant death syndrome cohort and in a patient with a long QT syndrome phenotype (Paludan-Müller et al. 2019. PubMed ID: 31043699; Kapplinger et al. 2009. PubMed ID: 19716085; Ackerman et al. 2001. PubMed ID: 11710892). This variant is reported in 0.00081% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-38622661-C-A). Taken together, this 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

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 15, 2022

- -

Long QT syndrome 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 14, 2001

- -

Congenital long QT syndrome Other:1

not provided, no classification provided

literature only

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

-

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 v4.3

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
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.089	N
M_CAP	Benign	0.080	D
MetaRNN	Uncertain	0.65	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.81	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.42	N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.49
Sift	Benign	0.57	T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.83	T;T;T;T;T;T;T;T;T
Polyphen		0.0010	B;B;.;B;.;B;B;.;.
Vest4		0.68
MutPred		0.78		Gain of glycosylation at A997 (P = 0.038);Gain of glycosylation at A997 (P = 0.038);Gain of glycosylation at A997 (P = 0.038);Gain of glycosylation at A997 (P = 0.038);Gain of glycosylation at A997 (P = 0.038);Gain of glycosylation at A997 (P = 0.038);Gain of glycosylation at A997 (P = 0.038);Gain of glycosylation at A997 (P = 0.038);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

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

LitVar

Other links and lift over

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