rs45620037

Variant names:

• chr3-38613787-G-A
• rs45620037
• NM_000335.5:c.659C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-38613787-G-A
• chr3-38613787-G-C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 3P and 7B. PM1 PP3 BP4_Moderate BP6 BS1

The NM_000335.5(SCN5A):​c.659C>T​(p.Thr220Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00084 in 1,611,012 control chromosomes in the GnomAD database, including 1 homozygotes. 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. T220A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00063 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00086 (1 hom.)
• Consequence: SCN5A NM_000335.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:7 B:7 O:1
• Conservation: PhyloP100: 10.0
• Publications: 59 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: Likely_benign. The variant received -4 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 13 uncertain in NM_000335.5
• PP3: Multiple lines of computational evidence support a deleterious effect 12: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, CardioboostArm, Dann, Eigen, M_CAP, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when CardioboostCm, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.12240586).
• BP6: Variant 3-38613787-G-A is Benign according to our data. Variant chr3-38613787-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 9396.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00063 (96/152320) while in subpopulation NFE AF = 0.000809 (55/68024). AF 95% confidence interval is 0.000638. There are 0 homozygotes in GnomAd4. There are 40 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_000335.5	c.659C>T	p.Thr220Ile	missense_variant	Exon 6 of 28	ENST00000423572.7	NP_000326.2
SCN5A	NM_001099404.2	c.703+188C>T		intron_variant	Intron 6 of 27	ENST00000413689.6	NP_001092874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000423572.7	c.659C>T	p.Thr220Ile	missense_variant	Exon 6 of 28	1	NM_000335.5	ENSP00000398266.2
SCN5A	ENST00000413689.6	c.703+188C>T		intron_variant	Intron 6 of 27	5	NM_001099404.2	ENSP00000410257.1

Frequencies

GnomAD3 genomes AF: 0.000631 AC: 96 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00349

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000808

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000663 AC: 162 AN: 244430 AF XY: 0.000611

Gnomad AFR exome AF: 0.0000669

Gnomad AMR exome AF: 0.000147

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00394

Gnomad NFE exome AF: 0.000631

Gnomad OTH exome AF: 0.000336

GnomAD4 exome AF: 0.000862 AC: 1258 AN: 1458692 Hom.: 1 Cov.: 30 AF XY: 0.000816 AC XY: 592 AN XY: 725282

African (AFR) AF: 0.0000897 AC: 3 AN: 33432

American (AMR) AF: 0.000135 AC: 6 AN: 44346

Ashkenazi Jewish (ASJ) AF: 0.0000384 AC: 1 AN: 26046

East Asian (EAS) AF: 0.00 AC: 0 AN: 39642

South Asian (SAS) AF: 0.00 AC: 0 AN: 85388

European-Finnish (FIN) AF: 0.00464 AC: 247 AN: 53220

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.000871 AC: 967 AN: 1110570

Other (OTH) AF: 0.000564 AC: 34 AN: 60288

GnomAD4 genome AF: 0.000630 AC: 96 AN: 152320 Hom.: 0 Cov.: 33 AF XY: 0.000537 AC XY: 40 AN XY: 74494

African (AFR) AF: 0.0000722 AC: 3 AN: 41568

American (AMR) AF: 0.00 AC: 0 AN: 15308

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

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

European-Finnish (FIN) AF: 0.00349 AC: 37 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000809 AC: 55 AN: 68024

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.000635 Hom.: 0

Bravo AF: 0.000310

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000476 AC: 4

ExAC AF: 0.000669 AC: 81

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:3

Mar 12, 2012

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.Thr220Ile (c.659 C>T) in the SCN5A gene (NM_198056.2) Given the abundance of case data, it seems likely that this variant contributes to disease in some fashion. What is challenging is determining whether it is sufficient on its own to cause disease or whether it is a modifer of some sort, given the presence of another variant in several reported cases and the presence of the variant in general population samples. Given this, we consider this variant a variant of uncertain significance, probably disease causing. The variant has been seen in one patient with sick sinus syndrome who was a compound heterozygote for this variant and a nonsense variant, one family with familial DCM, two patients with Brugada (one was a compound heterozygote for this variant and another missense variant), one patient with early-onset lone atrial fibrillation, two unrelated cases of pediatric onset atrial standstill (both cases were compound heterozygotes), one case of intrauterine death, one case of sudden unexplained death, and one case of irritable bowel syndrome. Using a candidate gene approach, Benson et al (2003) sequenced SCN5A in 10 patients with pediatric onset sick sinus syndrome from 7 families. Probands from three of the families were compound heterozygotes for two SCN5A variants (6 variants in total). One proband inherited p.Thr220Ile from his father and p.Arg1623Ter from his mother. His mother and two other maternal relatives who carry p.Arg1623Ter have first degree heart block. The two other maternal relatives also had prolonged QRS. His father was not available for study, however the paternal grandmother carried p.Thr220Ile and had a normal evaluation. Ancestry is not noted. The researchers are from various American academic medical centers. Olson et al (2005) observed the variant in one of 156 unrelated patients with DCM who underwent analysis of SCN5A. The patient had familial DCM (ischemic disease was ruled out) with atrial fibrillation and heart block. He never had documented ventricular tachycardia. The authors do not note if an arrhythmic phenotype preceded the cardiomyopathic phenotype. A first cousin had DCM, incomplete bundle branch block and also carried the variant. Ancestry is not noted. The patients were seen at Mayo in Minnesota or Latter Day Saints in Utah. The variant is reported in a compendium of SCN5A variants seen in individuals referred for Brugada syndrome genetic testing at various centers around the world (Kapplinger et al 2010). The authors note that patients were included if the physician who referred for genetic tesitng had made a possible or definite diagnosis of Brugada. Phenotype was not confirmed by the investigators so presumably some individuals included in the compendium do not in fact have Brugada syndrome. Two patients carried the variant. One patient was studied by the Brugada group and the other was studied by a Dutch group (likely same case reported by the Dutch group in Amin et al 2011). One patient also carried another SCN5A variant, p.Glu439Lys. He was diagnosed with Brugada at 26 years of age. Oleson et al (2012) observed the variant in 1 of 192 individuals with early onset lone atrial fibrillation. The patient had paroxysmal lone atrial fibrillation starting at 35 years of age. QTc was 422 ms, sodium blocking challenge (ex. Procainamide) was not done, and there was no family history of atrial fibrillation. Individual ancestry is not reported, but the subjects were recruited in Denmark. At the 2014 HRS meeting Baskar et al reported an 11yo girl with atrial standstill who was a compound heterozygote for this variant and a frameshift in SCN5A. The missense variant was inherited fr -

Feb 24, 2015

Blueprint Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 30, 2024

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: SCN5A c.659C>T (p.Thr220Ile) results in a non-conservative amino acid change located in the Ion-transport domain (IPR005821) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00065 in 250790 control chromosomes. The observed variant frequency is approximately 6.5-fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Arrhythmia phenotype (0.0001), suggesting that the variant is benign. c.659C>T has been reported in the literature in individuals affected with Arrhythmia and other cardiac phenotypes (e.g. Benson_2003, Olson_2005, Kapplinger_2010, Amin_2011, Olesen_2012, Baskar_2014, Celestino-Soper_2015, Ceyhan-Birsoy_2015, Marschall_2019, Raju_2019), but without strong evidence for causality. In several of the reports, the variant was identified in unaffected family members, indicating that the variant may not co-segregate with disease (e.g. Benson_2003, Baskar_2014). In addition, co-occurrences with other pathogenic/likely pathogenic variants have been reported [SCN5A c.3142_3153delins11 (Baskar_2014); SCN5A p.Arg1623X (Benson_2003); SCN5A c.3512-1G>C (internal sample)], providing supporting evidence for a benign role. Several publications report experimental evidence evaluating an impact on protein function and indicate that the variant may alter the properties or functions of sodium channels to varying degrees in-vitro (e.g. Benson_2003, Butters_2010, Gui_2010). The following publications have been ascertained in the context of this evaluation (PMID: 15671429, 20129283, 14523039, 20539757, 20448214, 22677073, 21273195, 24055113, 23571586, 22685113, 25637381, 24784157, 24762805, 25171853, 26636822, 27066507, 24613995, 31737537, 31337358, 32048431). ClinVar contains an entry for this variant (Variation ID: 9396). Based on the evidence outlined above, the variant was classified as likely benign. -

Jan 02, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Thr220Ile in exon 6 of SCN5A: This variant has was initially believed to be di sease causing based on its detection 12 probands with a range of SCN5-related di sorders (CSD, DCM, LQTS) and absence from controls (Benson 2003, Olson 2005, Kap plinger 2010, Oleson 2012, Crottie 2013, GeneDx, pers. comm.) as well as some in vitro functional data (Benson 2003, Butters 2010, Gui 2010). However, the varia nt is unlikely disease causing on its own based on its frequency in the general population (detected in 0.7% (30/4290) of European (Finnish) chromosomes and 0.1 % (46/43544) European (Non-Finnish) chromosomes screened by the Exome Aggregatio n Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs45620037). It remain s possible that the Thr220Ile variant represents a modifier or risk allele. -

not provided Uncertain:1 Benign:1

Oct 17, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in multiple patients with several different clinical phenotypes, including cardiomyopathy, sick sinus syndrome (SSS), Brugada syndrome, Long QT syndrome (LQTS), intrauterine fetal demise (IUFD), sudden death, and complete heart block; however, several of these individuals also harbored a second variant in SCN5A or in another gene, and some individuals who harbored only the p.(T220I) variant were clinically unaffected (PMID: 14523039, 15671429, 20129283, 21273195, 23571586, 24136861, 26636822, 26884609, 24762805, 26743238, 29709244, 27332903, 27066507, 32048431, 20539757, 25351510, 31737537, 22677073); Published studies examined the functional effect of the p.(T220I) variant, with the general conclusion that this variant impairs sodium ion channel function; however, it is unclear how these studies may translate to a pathogenic role in vivo (PMID: 20539757, 14523039, 20448214, 38196587); 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: 26636822, 24055113, 22685113, 20448214, 23414114, 24613995, 24784157, 25637381, 25171853, 20129283, 23571586, 21273195, 15671429, 24136861, 26884609, 28150151, 34426522, 30203441, 20539757, 14523039, 37937776, 29709244, 27332903, 26743238, 32048431, 31737537, 24762805, 25351510, 22677073, 35197637, 31337358, 27066507, 20384651, 21596231, 22581653, 24059039, 38196587) -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiac arrhythmia Benign:2

Sep 23, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 31, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dilated cardiomyopathy 1E Pathogenic:1

Jan 26, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sick sinus syndrome 1 Pathogenic:1

Jan 26, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

SCN5A-related disorder Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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 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. -

Primary familial dilated cardiomyopathy Uncertain:1

Apr 21, 2017

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

AV junctional rhythm Uncertain:1

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Long QT syndrome 3 Uncertain:1

Feb 17, 2018

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Long QT syndrome 3;C4551804:Brugada syndrome 1 Uncertain:1

Sep 20, 2021

Clinical Genomics Laboratory, Stanford Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Thr220Ile variant in the SCN5A gene has been previously reported in association with a range of cardiac disorders including Brugada syndrome, dilated cardiomyopathy, sick sinus syndrome, sudden cardiac death, atrial fibrillation, and complete heart block (Benson et al., 2003; Olson et al., 2005; Kapplinger et al., 2010; Amin et al., 2011; Olesen et al., 2012; Baskar et al., 2014; Celestino-Soper et al., 2015; Raju et al., 2019). However, in two families this variant co-occurred with a nonsense variant in SCN5A and in several instances this variant failed to segregate with disease (Benson et al., 2003; Baskar et al., 2014). This variant has been identified in 102/24,770 European Finnish chromosomes (197/275,834 chromosomes overall) by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Multiple studies on the functional impact of the p.Thr220Ile variant have suggested that this variant impairs sodium ion channel function (Benson et al., 2003; Butters et al., 2010; Gui et al., 2010). The threonine at position 220 is evolutionarily conserved. Computational tools predict that the p.Thr220Ile variant is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Thr220Ile variant is uncertain. However, population frequency data and conflicting case data suggests that this variant is more likely to be benign than pathogenic. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: PS3_Moderate; PP3; BS1; BP2] -

Cardiovascular phenotype Benign:1

May 18, 2021

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. -

Brugada 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 Brugada syndrome in the following publications (PMID:14523039;PMID:15671429;PMID:20129283;PMID:20448214;PMID:20539757;PMID:22685113). 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	0.93
CardioboostArm	Pathogenic	0.97
CardioboostCm	Benign	0.031
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	.;D;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.2	M;M;.
PhyloP100		10
PROVEAN	Pathogenic	-5.8	D;D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D;D
Sift4G	Benign	0.11	T;T;T
Polyphen		1.0	D;D;.
Vest4		0.95
MVP		0.98
ClinPred		0.14	T
GERP RS		4.3
Varity_R		0.91
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs45620037; hg19: chr3-38655278;