rs199473599

Positions:

• chr3-38566522-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_001099404.2(SCN5A):​c.3727G>A​(p.Asp1243Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000849 in 1,613,944 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1243E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000085 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:3 O:1
• Conservation: PhyloP100: 7.91

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.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SCN5A. . Gene score misZ 2.7504 (greater than the threshold 3.09). Trascript score misZ 4.7729 (greater than threshold 3.09). GenCC has associacion of gene with progressive familial heart block, type 1A, Brugada syndrome, familial sick sinus syndrome, short QT syndrome, paroxysmal familial ventricular fibrillation, progressive familial heart block, long QT syndrome 3, familial atrial fibrillation, catecholaminergic polymorphic ventricular tachycardia, dilated cardiomyopathy, dilated cardiomyopathy 1E, arrhythmogenic right ventricular cardiomyopathy, Brugada syndrome 1, atrial standstill, familial isolated dilated cardiomyopathy, familial long QT syndrome, sick sinus syndrome 1.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.813

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.3727G>A	p.Asp1243Asn	missense_variant	21/28	ENST00000413689.6
SCN5A	NM_000335.5	c.3724G>A	p.Asp1242Asn	missense_variant	21/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.3727G>A	p.Asp1243Asn	missense_variant	21/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.3724G>A	p.Asp1242Asn	missense_variant	21/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152164 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000143 AC: 36 AN: 251228 Hom.: 0 AF XY: 0.000125 AC XY: 17 AN XY: 135824

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00248

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000848 AC: 124 AN: 1461780 Hom.: 0 Cov.: 31 AF XY: 0.0000839 AC XY: 61 AN XY: 727196

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00226

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000342

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152164 Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8 AN XY: 74332

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000159 Hom.: 0

Bravo AF: 0.000125

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 17, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22885917, 20129283, 26173111, 23414114, 27153395, 30662450, 30193851, 22581653, 29709244, 26746457, 32533946, 34461752) -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 02, 2022	BS1, BS3_supporting, PP3 -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 18, 2021	Variant summary: SCN5A c.3727G>A (p.Asp1243Asn) results in a conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 254428 control chromosomes (gnomAD and publications). The observed variant frequency is approximately 1.4-fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Arrhythmia phenotype (0.0001), strongly suggesting that the variant is benign. c.3727G>A has been reported in the literature in individuals affected with Brugada Syndrome (BrS) (e.g. Kapplinger_2010, Selga_2015), including one proband with positive family history whose carrier family members had inducible, type 1 BrS ECG (i.e. could be induced upon drug challenge) while asymptomatic family members did not carry the variant (Selga_2015). The variant however was also reported in an individual with no apparent arrhythmia phenotype (Van Driest_2016). Furthermore, a co-occurrence with a pathogenic variant has been reported in at least one BrS patient (SCN5A c.1936delC, p.Gln646ArgfsX5; Kapplinger_2010), providing supporting evidence for a benign role. Experimental evidence evaluating an impact on protein function demonstrated the variant to have a peak current density of 114.7% relative to the wild-type, with the authors assigning a classification of Benign. Two ClinVar submitters (evaluation after 2014) cite the variant as likely benign and five ClinVar submitters (evaluation after 2014) cite it 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	Apr 25, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 5 probands from 1 paper, no segs in HGMD; ExAC: 12/66724 European chromosomes -

Brugada syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

The SCN5A c.3727G>A (p.Asp1243Asn) missense variant has been reported in at least three studies in which it is found in a total of 11 patients with Brugada syndrome including in three in a compound heterozygous state, and in eight in a heterozygous state (four of whom are related) (Kapplinger J et al 2010; Chockalingam P et al 2012; Selga E et al 2015). The second variant in the compound heterozygous patients is either a frameshift variant or a known pathogenic missense variant. The p.Asp1243Asn variant shows segregation in one family. The p.Asp1243Asn variant was absent from 1600 controls and is reported at a frequency of 0.00018 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence, the p.Asp1243Asn variant is classified as a variant of unknown significance but suspicious for pathogenicity for Brugada syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Dilated cardiomyopathy 1E Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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. -

Sick sinus syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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. -

Progressive familial heart block, type 1A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 04, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Cardiac arrhythmia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Aug 31, 2018

- -

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: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	Pathogenic	0.91
CardioboostCm	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	.;.;.;.;.;D;.;.;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	.;.;.;.;.;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-4.9	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.12	T;T;T;T;T;T;T;T;T
Polyphen		1.0	D;D;.;D;.;D;D;.;.
Vest4		0.99
MVP		0.99
MPC		1.2
ClinPred		0.81	D
GERP RS		4.4
Varity_R		0.88
gMVP		0.96

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: rs199473599; hg19: chr3-38608013;