chr3-38603887-G-T

Variant names:

• chr3-38603887-G-T
• rs36210423
• NM_001099404.2:c.1715C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001099404.2(SCN5A):​c.1715C>A​(p.Ala572Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00345 in 1,613,952 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A572F) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0040 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (48 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:27 O:1
• Conservation: PhyloP100: 0.497
• Publications: 56 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002438426).
• BP6: Variant 3-38603887-G-T is Benign according to our data. Variant chr3-38603887-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 67683.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00397 (605/152324) while in subpopulation NFE AF = 0.00291 (198/68034). AF 95% confidence interval is 0.00258. There are 7 homozygotes in GnomAd4. There are 392 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 SD,AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001099404.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN5A	NM_001099404.2	MANE Plus Clinical	c.1715C>A	p.Ala572Asp	missense	Exon 12 of 28	NP_001092874.1
	SCN5A	NM_000335.5	MANE Select	c.1715C>A	p.Ala572Asp	missense	Exon 12 of 28	NP_000326.2
	SCN5A	NM_198056.3		c.1715C>A	p.Ala572Asp	missense	Exon 12 of 28	NP_932173.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN5A	ENST00000413689.6	TSL:5 MANE Plus Clinical	c.1715C>A	p.Ala572Asp	missense	Exon 12 of 28	ENSP00000410257.1
	SCN5A	ENST00000423572.7	TSL:1 MANE Select	c.1715C>A	p.Ala572Asp	missense	Exon 12 of 28	ENSP00000398266.2
	SCN5A	ENST00000333535.9	TSL:1	c.1715C>A	p.Ala572Asp	missense	Exon 12 of 28	ENSP00000328968.4

Frequencies

GnomAD3 genomes AF: 0.00397 AC: 605 AN: 152206 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0363

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00291

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00491 AC: 1222 AN: 248994 AF XY: 0.00460

Gnomad AFR exome AF: 0.000258

Gnomad AMR exome AF: 0.000521

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0387

Gnomad NFE exome AF: 0.00295

Gnomad OTH exome AF: 0.00546

GnomAD4 exome AF: 0.00339 AC: 4960 AN: 1461628 Hom.: 48 Cov.: 31 AF XY: 0.00322 AC XY: 2343 AN XY: 727112

African (AFR) AF: 0.000269 AC: 9 AN: 33480

American (AMR) AF: 0.000514 AC: 23 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.0378 AC: 2018 AN: 53336

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00243 AC: 2705 AN: 1111858

Other (OTH) AF: 0.00338 AC: 204 AN: 60372

GnomAD4 genome AF: 0.00397 AC: 605 AN: 152324 Hom.: 7 Cov.: 32 AF XY: 0.00526 AC XY: 392 AN XY: 74458

African (AFR) AF: 0.000265 AC: 11 AN: 41578

American (AMR) AF: 0.000523 AC: 8 AN: 15310

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0363 AC: 385 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00291 AC: 198 AN: 68034

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00159 Hom.: 2

Bravo AF: 0.00119

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000245 AC: 1

ESP6500EA AF: 0.00239 AC: 20

ExAC AF: 0.00429 AC: 519

EpiCase AF: 0.00169

EpiControl AF: 0.00231

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:27 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:8

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 03, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SCN5A: BS1, BS2

Apr 22, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 23008441, 22378279, 20403459, 12820704, 27243970, 27153395, 27287068, 27930701, 18452873, 28781330, 29672598, 29214556, 28988457, 29032884, 32880476)

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Apr 29, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 18, 2018

Athena Diagnostics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:5

Dec 11, 2017

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The SCN5A c.1715C>A (p.Ala572Asp) variant located in the cytoplasmic region between domains I and II of Nav1.5 (Ortiz-Bonnin_2016) involves the alteration of a non-conserved nucleotide and 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). Functional studies show the variant could have a gain-of-function implication (Ortiz-Bonin_2016), an affect on recovery time (Albert_2008), or acts like wild type SCN5A, although in the context of a certain genotype such as the SCN5A polymorphism H588R moderate dysfunction was observed (Tester_2010). Overall, the authors indicate that the variant is not associated with the LQTS phenotype. This variant was found in 1486/279922 control chromosomes (23 homozygotes), predominantly observed in the European (Finnish) subpopulation at a frequency of 0.038676 (997/25778). This frequency is about 387 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 European (Finnish) origin. Multiple publications have cited the variant of interest in affected individuals. One family reported by Paulussen_2003 found the variant to be in two unaffected family members, with the proband carrying the variant and another pathogenic KCNQ1 variant, V254M, while Ortiz-Bonnin_2016 reported an affected family member that did not carry the variant of interest. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/benign. Taken together, based on reports of co-occurrence with a pathogenic variant in another gene, lack of co-segregation with disease phenotype, and an unexpectedly high frequency in controls, this variant is classified as benign, although the possibility of a modifier effect in certain genetic backgrounds cannot be ruled out.

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Aug 12, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Ala572Asp in exon 12 of SCN5A: This variant was identified in 3.9% (257/6618) Finnish chromosomes including 5 homozygous individuals by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org/; dbSNP rs36210423) and was re ported at slightly lower frequencies in control cohorts across multiple studies investigating the genetic cause of LQTS and related clinical entities (Mank-Seym our 2006, Arnestad 2007, Albert 2008, Tester 2010). There is a possibility that the p.Ala572Asp variant may have a minor impact on protein function (Albert 2008 , Tester 2010, Koval 2012); however, these in vitro assays may not accurately re present biological function. Although a modifying role in disease cannot be full y excluded, this variant is likely benign.

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ventricular fibrillation, paroxysmal familial, type 1 Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Aug 29, 2014

Blueprint Genetics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Brugada syndrome 1 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Cardiac arrest Benign:1

Aug 29, 2014

Blueprint Genetics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Arrhythmogenic right ventricular cardiomyopathy Benign:1

Aug 16, 2017

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cardiomyopathy Benign:1

Mar 03, 2023

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 Benign:1

Sep 06, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dilated cardiomyopathy 1E Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Sick sinus syndrome 1 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Progressive familial heart block, type 1A Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Left ventricular noncompaction cardiomyopathy Benign:1

Aug 29, 2014

Blueprint Genetics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Cardiovascular phenotype Benign:1

Oct 01, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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.

Long QT syndrome 3 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Cardiac arrhythmia Benign:1

Mar 19, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Congenital long QT syndrome 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 as associated with Long QT syndrome in the following publications (PMID:12354768;PMID:12820704;PMID:15466642;PMID:15840476;PMID:17161064;PMID:17210839;PMID:18071069;PMID:20403459). 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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.52	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.50
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.27
Sift	Benign	0.44	T
Sift4G	Benign	0.23	T
Polyphen		0.022	B
Vest4		0.38
MVP		0.48
MPC		0.64
ClinPred		0.015	T
GERP RS		3.2
Varity_R		0.098
gMVP		0.71
Mutation Taster		=96/4	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: rs36210423; hg19: chr3-38645378;