3-38598927-C-T

Variant names:

• chr3-38598927-C-T
• rs199473140
• NM_001099404.2:c.2014G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001099404.2(SCN5A):​c.2014G>A​(p.Ala672Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000393 in 1,613,816 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/24 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. A672L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00041 (9 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:7 O:1
• Conservation: PhyloP100: 2.42
• Publications: 8 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008682013).
• BP6: Variant 3-38598927-C-T is Benign according to our data. Variant chr3-38598927-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 67704.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000236 (36/152282) while in subpopulation SAS AF = 0.00685 (33/4818). AF 95% confidence interval is 0.00501. There are 0 homozygotes in GnomAd4. There are 22 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 9 SD,AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.2014G>A	p.Ala672Thr	missense_variant	Exon 13 of 28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.2014G>A	p.Ala672Thr	missense_variant	Exon 13 of 28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.2014G>A	p.Ala672Thr	missense_variant	Exon 13 of 28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.2014G>A	p.Ala672Thr	missense_variant	Exon 13 of 28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00684

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000795 AC: 198 AN: 248926 AF XY: 0.00110

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000377

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000356

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000410 AC: 599 AN: 1461534 Hom.: 9 Cov.: 31 AF XY: 0.000630 AC XY: 458 AN XY: 727042

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.000313 AC: 14 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00645 AC: 556 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53362

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5686

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1111840

Other (OTH) AF: 0.000232 AC: 14 AN: 60364

GnomAD4 genome AF: 0.000236 AC: 36 AN: 152282 Hom.: 0 Cov.: 32 AF XY: 0.000296 AC XY: 22 AN XY: 74442

African (AFR) AF: 0.00 AC: 0 AN: 41568

American (AMR) AF: 0.0000654 AC: 1 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00685 AC: 33 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000893 Hom.: 0

Bravo AF: 0.0000869

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000881 AC: 107

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:7 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3 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 in the following publications (PMID:19841300;PMID:20129283). -

Jan 16, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 22, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The SCN5A c.2014G>A (p.Ala672Thr) variant involves the alteration of a conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant (SNPsandGO and MutationTaster not captured due to low reliability index). This variant was found in 111/140944 control chromosomes (1 homozygote), predominantly observed in the South Asian subpopulation at a frequency of 0.005815 (96/16510). This frequency is about 58 times the estimated maximal expected allele frequency of a pathogenic SCN5A variant (0.0001), suggesting this is likely a benign polymorphism found primarily in the populations of South Asian origin. The variant has been reported in the literature, mostly in controls, and without strong evidence for causality. In addition, one clinical diagnostic laboratory has classified this variant as likely benign. Taken together, this variant is classified as likely benign. -

May 08, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 20129283, 19841300, 25351510) -

Cardiac arrhythmia Benign:2

Sep 23, 2024

All of Us Research Program, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 29, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Apr 14, 2011

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Ala672Thr (A672T; c.2014 G>A) in the SCN5A gene This variant has not previously been reported in any individuals with LQTS or Brugada syndrome. It has, however, been seen in controls of 3 different ancestries. In total this variant has been seen in 3 out of ~8800 individuals from published controls and publicly available population datasets. In terms of Caucasian controls ethnically-matched to our patient, it has been seen in 1 out of ~5328 individuals. Kapa et al. from Ackerman’s group (2009; also Kapplinger et al. 2010) found the variant in 1 control individual of Asian ancestry out of ~1300 mixed-race controls (649 of which were Caucasian). This same paper reports that 3% of controls were positive for a variant in SCN5A. This variant is also present in 1 European American individual in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals (as of 1/7/2013). It is present in dbSNP as rs199473140, and the source of this is 1 individual of Mexican ancestry in 1000 Genomes. (1000 Genomes contains 1092 individuals, 379 of which are of European ancestry.) GeneDx did not report controls. Variation at a nearby residues (plus or minus 10 amino acids) has been associated with disease, suggesting the possible functional importance of this region of the protein: L673P (LQT3) is in HGMD according to GeneDx; other variants include R680H (associated with SIDS; also with increased sodium current in vitro, but only under conditions of internal acidosis) and H681P (Brugada) (UniProtKB; IRCCS Fondazione Salvatore Maugeri database, citing Arnestad et al. 2007 and Priori et al. 2002). This is a non-conservative amino acid change, resulting in the replacement of a nonpolar, hydrophobic alanine with a polar, hydrophilic threonine. The alanine at this location is not highly conserved among vertebrates; in fact, the reference amino acid is a threonine in 6 species of fish. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “benign” with a score of 0.005. SIFT predicts it to be “tolerated” with a score of 1. -

Primary dilated cardiomyopathy Uncertain:1

-

Genetics and Genomics Program, Sidra Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

SCN5A-related disorder Benign:1

Apr 09, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype Benign:1

Sep 06, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
CardioboostArm	Benign	0.0000037
CardioboostCm	Benign	0.0013
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	23
DANN	Benign	0.40
DEOGEN2	Benign	0.34	.;.;.;.;.;T;.;.;.
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.84	.;T;T;T;T;T;T;.;T
M_CAP	Pathogenic	0.51	D
MetaRNN	Benign	0.0087	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.042	D
MutationAssessor	Benign	0.67	.;N;.;.;.;N;.;.;.
PhyloP100		2.4
PrimateAI	Benign	0.46	T
PROVEAN	Benign	1.5	N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.29
Sift	Benign	1.0	T;T;T;T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T;T
Polyphen		0.0020	B;B;.;B;.;B;B;.;.
Vest4		0.27
MVP		0.68
MPC		0.34
ClinPred		0.027	T
GERP RS		4.1
Varity_R		0.068
gMVP		0.74
Mutation Taster		=98/2	polymorphism

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: rs199473140; hg19: chr3-38640418;