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rs41315493

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP4_StrongBP6_Very_StrongBS2

The NM_001099404.2(SCN5A):c.5851G>T(p.Val1951Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00405 in 152224 control chromosomes in the gnomAD Genomes database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 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. V1951M) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0041 ( 6 hom., cov: 33)
Exomes 𝑓: 0.0066 ( 26 hom. )

Consequence

SCN5A
NM_001099404.2 missense

Scores

2
13

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:26O:1

Conservation

PhyloP100: 0.927

Links

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

PP2
?
Missense variant where missense usually causes diseases, SCN5A
BP4
?
Computational evidence support a benign effect (MetaRNN=0.0035488904).
BP6
?
Variant 3-38550521-C-A is Benign according to our data. Variant chr3-38550521-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 36765. Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38550521-C-A is described in Lovd as [Benign].
BS2
?
High Homozygotes in GnomAd at 6 AD,AR,Digenic gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SCN5ANM_001099404.2 linkuse as main transcriptc.5851G>T p.Val1951Leu missense_variant 28/28 ENST00000413689.6
SCN5ANM_000335.5 linkuse as main transcriptc.5848G>T p.Val1950Leu missense_variant 28/28 ENST00000423572.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SCN5AENST00000413689.6 linkuse as main transcriptc.5851G>T p.Val1951Leu missense_variant 28/285 NM_001099404.2 P4
SCN5AENST00000423572.7 linkuse as main transcriptc.5848G>T p.Val1950Leu missense_variant 28/281 NM_000335.5 A1Q14524-2

Frequencies

GnomAD3 genomes
AF:
0.00405
AC:
617
AN:
152224
Hom.:
6
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00347
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0270
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00328
Gnomad SAS
AF:
0.00248
Gnomad FIN
AF:
0.000377
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.000265
Gnomad OTH
AF:
0.00383
GnomAD3 exomes
AF:
0.00662
AC:
1633
AN:
246710
Hom.:
26
AF XY:
0.00520
AC XY:
696
AN XY:
133972
show subpopulations
Gnomad AFR exome
AF:
0.00358
Gnomad AMR exome
AF:
0.0405
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00298
Gnomad SAS exome
AF:
0.00181
Gnomad FIN exome
AF:
0.000561
Gnomad NFE exome
AF:
0.000376
Gnomad OTH exome
AF:
0.00467
GnomAD4 exome
AF:
0.00178
AC:
2598
AN:
1459324
Hom.:
46
AF XY:
0.00158
AC XY:
1145
AN XY:
725558
show subpopulations
Gnomad4 AFR exome
AF:
0.00281
Gnomad4 AMR exome
AF:
0.0405
Gnomad4 ASJ exome
AF:
0.0000384
Gnomad4 EAS exome
AF:
0.00305
Gnomad4 SAS exome
AF:
0.00163
Gnomad4 FIN exome
AF:
0.000881
Gnomad4 NFE exome
AF:
0.000204
Gnomad4 OTH exome
AF:
0.00257
Alfa
AF:
0.000820
Hom.:
0
Bravo
AF:
0.00595
ESP6500AA
AF:
0.00457
AC:
19
ESP6500EA
AF:
0.000596
AC:
5
ExAC
AF:
0.00525
AC:
635

ClinVar

Significance: Benign/Likely benign
Submissions summary: Uncertain:1Benign:26Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1Benign:8
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jul 05, 2013- -
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, Part of Exact Sciences-- -
Benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMar 19, 2012p.Val1951Leu in Exon 28 of SCN5A: This variant is not expected to have clinical significance because it has been identified in 6.5% (6/92) of chromosomes from a population in the dbSNP database (http://www.ncbi.nlm.nih.gov/projects/SNP; rs4 1315493). -
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Uncertain significance, no assertion criteria providedclinical testingStanford Center for Inherited Cardiovascular Disease, Stanford UniversityMar 26, 2015Note 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.Val1951Leu (c.5851G>T) in the SCN5A gene. This variant has been reported in published literature. Priori et al (2004) reported the presence of the variant in one Caucasian individual who had a Brugada syndrome diagnosis. It was also reported in a case of SIDS (Arnestad et al 2007). In vitro studies have been conflicting, with some reporting an abnormal biophysical phenotype (Wang er al 2008) and others reporting normal function (Tan et al 2005). Arnestad et al commented that this variant could exhibit ethnic-dependent phenotype expression (2007). A nonpolar, neutral Valine is replaced with a nonpolar, neutral Leucine at position 1951 in the SCN5A gene. The change does not affect the net charge of the polypeptide. This codon is not well conserved across species. In 2004, Darbar et al sequenced the SCN5A coding region of 378 individuals with Atrial fibrillation (alone or in association with another cardiac condition), they identified one Caucasian individual with atrial fibrillation and HCM who harbored a variant in the same codon (p.Val1951Met). In this patient’s family the variant did co segregate with phenotype in the patient’s father, paternal grandmother and 2 siblings. Priori et al (2004) report this variant was not found in 400 Caucasian presumably healthy controls. Genedx did not find the variant in 200 Caucasian and African American controls. However, the p.Val1951Leu variant has been reported in 6.7% of normal Hispanics (Ackerman et al 2005). Darbar et al (2008) reported that the p.Val1951Leu variant was observed in 7 out of 720 presumably healthy controls of both Caucasian and African American descent. In addition, Kapplinger et al (2010) reported that the p.Val1951Leu variant is found in highest percentage in Hispanic controls, then Asian, African America and “other” presumably healthy controls. They classified this variant as a polymorphism. Given these data, the impact of this variant on arrhythmic risk is unclear. It is possible that it is a common variant (i.e. >5%) in several ancestral groups and that it was identified in the published cases of SIDS and Brugada because of its prevalence, not because of its pathogenicity. -
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Benign, criteria provided, single submitterclinical testingGenomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of PhiladelphiaJul 01, 2015- -
not provided Benign:3Other:1
not provided, no classification providedliterature onlyCardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust-This variant has been reported in the following publications (PMID:10807545;PMID:11901046;PMID:15851227;PMID:16379539;PMID:17210839;PMID:18426444;PMID:19841300;PMID:21109022;PMID:20129283;PMID:15992732;PMID:17210841;PMID:22378279). -
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesMar 08, 2022- -
Benign, criteria provided, single submitterclinical testingAthena Diagnostics IncOct 18, 2017- -
Likely benign, criteria provided, single submitterclinical testingMolecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute-- -
Brugada syndrome Benign:2
Benign, criteria provided, single submitterclinical testingInvitaeNov 03, 2022- -
Likely benign, no assertion criteria providedresearchCSER _CC_NCGL, University of WashingtonJun 01, 2014- -
Ventricular tachycardia;CN225662:Pulmonary valve stenosis (rare) Benign:1
Likely benign, no assertion criteria providedclinical testingBlueprint GeneticsAug 15, 2014- -
Brugada syndrome 1 Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaFeb 05, 2018This 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. -
Ventricular fibrillation, paroxysmal familial, type 1 Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaFeb 05, 2018This 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. -
Cardiomyopathy Benign:1
Benign, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioDec 13, 2021- -
Atrial fibrillation;C1142166:Brugada syndrome Benign:1
Likely benign, criteria provided, single submitterresearchBiesecker Lab/Clinical Genomics Section, National Institutes of HealthJun 24, 2013- -
Dilated cardiomyopathy 1E Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaFeb 05, 2018This 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
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaFeb 05, 2018This 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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Progressive familial heart block, type 1A Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaFeb 05, 2018This 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. -
Long QT syndrome;C0878544:Cardiomyopathy Benign:1
Benign, criteria provided, single submitterclinical testingCenter for Advanced Laboratory Medicine, UC San Diego Health, University of California San DiegoJun 11, 2019- -
Long QT syndrome Benign:1
Benign, no assertion criteria providedclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJan 08, 2015Variant Summary: c.5848G>T is a missense variant that occurrs at a non-conserved position, and 5/5 in silico tools predict benign outcome of this variant. The observed allele frequency in an ethnically diverse set of control chromosomes is 102/24,730 (1/242; 0.41%; 2 homozgotes reported); this frequency is significantly higher than the maximal expected allele frequency of 1/48,000 for a pathogenic SCN5A variant for LQTS/SCD or 1/6,000 for BrS. The ExAC population reports the variant in 477/11,174 (1/23; 4.27%) Latino chromosomes, with 6 homozygotes. These allele frequencies strongly suggest that the variant is benign. Further support of a benign outcome is a reported Korean family (Shin et al, 2003) where this variant did not cosegregate with disease, and a sudden cardiac death patient whom also carried another potentially pathogenic variant in the KCNE1 gene (Tester et al 2012). Functional studies results are in conflict, but suggest that the variant may have a modifying effect dependent upon the presence of other SCN5A variants. Most in vitro studies have shown that the variant has no significant effect on in vitro function when in isolation. V1951L did not exhibit an overt LQT3-like phenotype or an overt loss of function phenotype, therefore its involvement in the settings of either LQT3 or Brugada syndrome is not substantiated. Furthermore, although the authors reported other "significant functional disturbances" , the results and conclusions of these findings are not applicable to the mechanism of action, and physiologic consequences or presentation of disease (i.e., LQT3 or Brugada). Collectively, although this variant may play a role in the context of complex or oligogenic alleles, in isolation there is no evidence to suggest that it significantly impairs SCN5A function, several reputable sources classify the variant as benign, and the significantly higher oberseved allele frequency compared to the maximimal expected allele frequency of a pathogenic SCN5A variant indicate that the in vivo consequence of this variant is, indeed, benign. -
Long QT syndrome 3 Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaFeb 05, 2018This 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. -
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsAug 05, 2015This alteration is classified as benign based on a combination of the following: 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
Benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthMar 19, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.27
T
BayesDel_noAF
Benign
-0.13
Cadd
Benign
1.2
Dann
Benign
0.85
Eigen
Benign
-1.0
Eigen_PC
Benign
-0.88
FATHMM_MKL
Uncertain
0.79
D
MetaRNN
Benign
0.0035
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.45
T
MutationTaster
Benign
1.0
N;N;N;N;N;N;N;N;N;N
PrimateAI
Benign
0.30
T
PROVEAN
Benign
0.24
N;N;N;N;N;N;N;N;N
REVEL
Uncertain
0.32
Sift
Benign
0.19
T;T;T;T;T;T;T;T;T
Sift4G
Benign
0.29
T;T;T;T;T;T;T;T;T
Polyphen
0.0
B;B;.;B;.;B;B;.;.
Vest4
0.14
MutPred
0.76
.;.;Loss of helix (P = 0.0558);.;.;Loss of helix (P = 0.0558);.;.;.;
MVP
0.77
MPC
0.50
ClinPred
0.0027
T
GERP RS
-0.53
Varity_R
0.051
gMVP
0.18

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

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

Other links and lift over

dbSNP: rs41315493; hg19: chr3-38592012; API