rs137854603

chr3-38550602-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PM2 PP2 BP4

The NM_001099404.2(SCN5A):c.5770G>A(p.Ala1924Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000254 in 1,613,950 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. A1924S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:4 B:1 O:1
• Conservation: PhyloP100: 6.16

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 4 ACMG points.

• PM1: In a helix (size 30) in uniprot entity SCN5A_HUMAN there are 7 pathogenic changes around while only 2 benign (78%) in NM_001099404.2
• 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=0.39713567).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.5770G>A	p.Ala1924Thr	missense_variant	28/28	ENST00000413689.6
SCN5A	NM_000335.5	c.5767G>A	p.Ala1923Thr	missense_variant	28/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.5770G>A	p.Ala1924Thr	missense_variant	28/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.5767G>A	p.Ala1923Thr	missense_variant	28/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152248 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000602 AC: 15 AN: 249238 Hom.: 0 AF XY: 0.0000444 AC XY: 6 AN XY: 135208

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000253 AC: 37 AN: 1461702 Hom.: 0 Cov.: 32 AF XY: 0.0000234 AC XY: 17 AN XY: 727136

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.000918

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152248 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74382

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000137 Hom.: 0

Bravo AF: 0.0000416

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.0000413 AC: 5

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:4 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Brugada syndrome 1 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Dec 10, 2018	The SCN5A c.5770G>A (p.Ala1924Thr) missense variant has described in four studies and found in a heterozygous state in a total of three individuals affected with Brugada syndrome and in a homozygous state in a pair of identical twins affected with sinus node dysfunction (Rook et al. 1999; Meregalli et al. 2009; Amin et al. 2011; Chiang et al. 2015). The p.Ala1924Thr variant was present in one of 1400 controls (Kapplinger et al. 2010) and is reported at a frequency of 0.001084 in the Ashkenazi Jewish population of the Genome Aggregation Database. Functional studies in Xenopus oocytes demonstrated that the variant significantly affected the inward sodium current causing an increase during the action potential upstroke (Rook et al. 1999). Tan et al. (200) demonstrated that the p.Ala1924Thr increased the rate of fast activation of the sodium channel whilst inhibiting the slow activation induced by the calcium-dependent binding of calmodulin. Based on the evidence, the p.Ala1924Thr variant is classified as likely pathogenic for Brugada syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1999	- -

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 29, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 15, 2021	Observed in several individuals with Brugada syndrome in the published literature (Rook et al., 1999; Smits et al., 2002; Tan et al., 2002; Meregalli et al., 2009; Kapplinger et al., 2010; Amin et al., 2011; Nof et al., 2019); Reported in ClinVar (ClinVar Variant ID# 9381; Landrum et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25758664, 15795161, 16472137, 11893549, 27262167, 19171938, 12106943, 25904541, 33306788, 23104914, 17993328, 11673053, 19251209, 20129283, 21273195, 11807557, 11420310, 11123251, 12393785, 19027780, 14753626, 21454796, 10690282, 26111534, 9950665, 14961552, 11410597, 10940383, 12639704, 23414114, 31231243, 30662450, 21167176, 16505387, 33131149) -

Long QT syndrome;C1142166:Brugada syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health

Aug 06, 2021

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 19, 2019

The c.5770G>A (p.A1924T) alteration is located in exon 28 (coding exon 27) of the SCN5A gene. This alteration results from a G to A substitution at nucleotide position 5770, causing the alanine (A) at amino acid position 1924 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Cardiac arrhythmia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Feb 22, 2023

This missense variant replaces alanine with threonine at codon 1924 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant affects sodium channel activation and inactivation properties (PMID: 10690282, 11807557, 23104914) and reduces binding affinity for calmodulin (PMID: 16505387). This variant has been reported in an individual affected with Brugada syndrome (PMID: 10690282), in homozygous identical twins with sinus node dysfunction and atrial tachycardia (PMID: 26111534), as well as in a control individual (PMID: 25904541). This variant has been identified in 16/280642 chromosomes (12/10352 Ashkenazi Jewish chromosomes, 0.11%) in the general population by the Genome Aggregation Database (gnomAD). In summary, although this variant has been reported in multiple affected individuals, this variant also occurs at an appreciable frequency in the general population. 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 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 Brugada syndrome in the following publications (PMID:10690282;PMID:12106943;PMID:19251209;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	Uncertain	0.36
CardioboostArm	Uncertain	0.73
CardioboostCm	Benign	0.042
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.25
Cadd	Uncertain	24
Dann	Pathogenic	1.0
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.43	D
MetaRNN	Benign	0.40	T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.2	N;N;N;N;N;N;N;N;N
REVEL	Pathogenic	0.74
Sift	Benign	0.058	T;T;T;T;D;T;T;D;D
Sift4G	Benign	0.26	T;T;T;T;T;T;T;T;T
Polyphen		0.97	D;P;.;D;.;P;D;.;.
Vest4		0.59
MVP		0.89
MPC		1.4
ClinPred		0.28	T
GERP RS		4.9
Varity_R		0.28
gMVP		0.59

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: rs137854603; hg19: chr3-38592093;