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rs45620037

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PM1PM2PP2PP3BP4_Moderate

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

Scores

13
2
4

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:6B:6O:1

Conservation

PhyloP100: 10.0
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 10 uncertain in NM_000335.5
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant where missense usually causes diseases, SCN5A
PP3
Multiple lines of computational evidence support a deleterious effect 11: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, CardioboostArm, Dann, Eigen, M_CAP, phyloP100way_vertebrate, PROVEAN, REVEL [when CardioboostCm, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
BP4
Computational evidence support a benign effect (MetaRNN=0.12240586).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SCN5ANM_000335.5 linkuse as main transcriptc.659C>T p.Thr220Ile missense_variant 6/28 ENST00000423572.7
SCN5ANM_001099404.2 linkuse as main transcriptc.703+188C>T intron_variant ENST00000413689.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SCN5AENST00000423572.7 linkuse as main transcriptc.659C>T p.Thr220Ile missense_variant 6/281 NM_000335.5 A1Q14524-2
SCN5AENST00000413689.6 linkuse as main transcriptc.703+188C>T intron_variant 5 NM_001099404.2 P4

Frequencies

GnomAD3 genomes
AF:
0.000631
AC:
96
AN:
152202
Hom.:
0
Cov.:
33
show subpopulations
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
GnomAD3 exomes
AF:
0.000663
AC:
162
AN:
244430
Hom.:
0
AF XY:
0.000611
AC XY:
81
AN XY:
132490
show subpopulations
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 SAS 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
show subpopulations
Gnomad4 AFR exome
AF:
0.0000897
Gnomad4 AMR exome
AF:
0.000135
Gnomad4 ASJ exome
AF:
0.0000384
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00464
Gnomad4 NFE exome
AF:
0.000871
Gnomad4 OTH exome
AF:
0.000564
GnomAD4 genome
AF:
0.000630
AC:
96
AN:
152320
Hom.:
0
Cov.:
33
AF XY:
0.000537
AC XY:
40
AN XY:
74494
show subpopulations
Gnomad4 AFR
AF:
0.0000722
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00349
Gnomad4 NFE
AF:
0.000809
Gnomad4 OTH
AF:
0.000474
Alfa
AF:
0.000619
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:2Uncertain:6Benign:6Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:1Benign:3
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJan 30, 2024Variant 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. -
Uncertain significance, no assertion criteria providedclinical testingStanford Center for Inherited Cardiovascular Disease, Stanford UniversityMar 12, 2012Note 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 -
Likely benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJan 02, 2015p.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. -
Likely benign, criteria provided, single submitterclinical testingBlueprint GeneticsFeb 24, 2015- -
not provided Uncertain:1Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeJan 27, 2024- -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJun 20, 2023Reported 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 (PMID: 20539757, 14523039, 20448214); however, it is unclear how these studies may translate to a pathogenic role in vivo; 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, 29709244, 27332903, 26743238, 32048431, 31737537, 24762805, 25351510, 22677073, 35197637, 31337358, 27066507, 20384651, 21596231, 22581653, 24059039) -
Dilated cardiomyopathy 1E Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMJan 26, 2005- -
Sick sinus syndrome 1 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMJan 26, 2005- -
SCN5A-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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
Uncertain significance, criteria provided, single submitterclinical testingMolecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart InstituteApr 21, 2017- -
AV junctional rhythm Uncertain:1
Uncertain significance, no assertion criteria providedresearchCSER _CC_NCGL, University of WashingtonJun 01, 2014- -
Long QT syndrome 3 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCenter For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And ColleaguesFeb 17, 2018- -
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsMay 18, 2021This 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 submitterclinical testingColor Diagnostics, LLC DBA Color HealthAug 31, 2018- -
Brugada syndrome Other:1
not provided, no classification providedliterature onlyCardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust-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
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;.
MutationTaster
Benign
1.0
A;A;A;A;A;A;A;A;A;A
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

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs45620037; hg19: chr3-38655278; API