3-38550368-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001099404.2(SCN5A):c.6004G>A(p.Ala2002Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000241 in 1,538,218 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A2002A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000059 (1 hom., cov: 33)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:8
• Conservation: PhyloP100: 1.62

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SCN5A
• BP4: Computational evidence support a benign effect (MetaRNN=0.084561825).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.6004G>A	p.Ala2002Thr	missense_variant	28/28	ENST00000413689.6
SCN5A	NM_000335.5	c.6001G>A	p.Ala2001Thr	missense_variant	28/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.6004G>A	p.Ala2002Thr	missense_variant	28/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.6001G>A	p.Ala2001Thr	missense_variant	28/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152082 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000307 AC: 6 AN: 195482 Hom.: 0 AF XY: 0.0000291 AC XY: 3 AN XY: 103102

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000369

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000558

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000439

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000202 AC: 28 AN: 1386136 Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 14 AN XY: 679300

Gnomad4 AFR exome AF: 0.0000316

Gnomad4 AMR exome AF: 0.0000275

Gnomad4 ASJ exome AF: 0.0000472

Gnomad4 EAS exome AF: 0.0000514

Gnomad4 SAS exome AF: 0.0000271

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000168

Gnomad4 OTH exome AF: 0.0000526

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152082 Hom.: 1 Cov.: 33 AF XY: 0.0000942 AC XY: 7 AN XY: 74304

Gnomad4 AFR AF: 0.0000966

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.0000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 31, 2023	Variant summary: SCN5A c.6004G>A (p.Ala2002Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.1e-05 in 195482 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6004G>A has been reported in the literature in at least one individual affected with Brugada syndrome (e.g., Ciconte_2021). This report does not provide unequivocal conclusions about association of the variant with Arrhythmia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 33221895). Six submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 04, 2015	The p.Ala2002Thr variant in SCN5A has not been previously reported in individual s with cardiomyopathy or in large population studies. Alanine (Ala) at position 2002 is not conserved in mammals or evolutionarily distant species and 1 mammal (pika) carries a threonine (Thr) at this position, raising the possibility that this change may be tolerated. Additional computational prediction tools also sug gest that the p.Ala2002Thr variant may not impact the protein, though this infor mation is not predictive enough to rule out pathogenicity. In summary, the clini cal significance of the p.Ala2002Thr variant is uncertain. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 27, 2023	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2002 of the SCN5A protein (p.Ala2002Thr). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of Brugada syndrome (PMID: 33221895). ClinVar contains an entry for this variant (Variation ID: 229236). 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. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 18, 2023	Reported among a cohort of individuals with Brugada syndrome (Ciconte et al., 2021); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 33221895) -

Cardiac arrhythmia Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 20, 2023	This missense variant replaces alanine with threonine at codon 2002 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least one individual affected with Brugada syndrome (PMID: 33221895). This variant has been identified in 6/195482 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	Nov 30, 2023	This missense variant replaces alanine with threonine at codon 2002 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least one individual affected with Brugada syndrome (PMID: 33221895). This variant has been identified in 6/195482 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. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 13, 2021

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 12, 2021

The p.A2002T variant (also known as c.6004G>A), located in coding exon 27 of the SCN5A gene, results from a G to A substitution at nucleotide position 6004. The alanine at codon 2002 is replaced by threonine, an amino acid with similar properties, and is located in the cytoplasmic C-terminal region. This amino acid position is not well conserved in available vertebrate species, and threonine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
CardioboostArm	Benign	0.0000042
CardioboostCm	Benign	0.0034
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	15
Dann	Uncertain	1.0
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.031	N
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.085	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.21	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.0	N;N;N;N;N;N;N;N;N
REVEL	Benign	0.27
Sift	Benign	0.11	T;T;T;T;D;T;T;D;D
Sift4G	Benign	0.29	T;T;T;T;T;T;T;T;T
Polyphen		0.88	P;P;.;P;.;B;P;.;.
Vest4		0.075
MVP		0.52
MPC		0.50
ClinPred		0.067	T
GERP RS		4.6
Varity_R		0.039
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs771018427; hg19: chr3-38591859; COSMIC: COSV100351198; COSMIC: COSV100351198;