chr3-38622446-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP3BP6

The NM_001099404.2(SCN5A):c.436G>A(p.Val146Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,612,196 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. V146A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

SCN5A
NM_001099404.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3O:1

Conservation

PhyloP100: 3.10

Publications

9 publications found

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]

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

SCN5A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.764

BP6

Variant 3-38622446-C-T is Benign according to our data. Variant chr3-38622446-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 67886. Variant chr3-38622446-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 67886. Variant chr3-38622446-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 67886. Variant chr3-38622446-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 67886. Variant chr3-38622446-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 67886. Variant chr3-38622446-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 67886. Variant chr3-38622446-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 67886. Variant chr3-38622446-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 67886. Variant chr3-38622446-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 67886. Variant chr3-38622446-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 67886. Variant chr3-38622446-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 67886. Variant chr3-38622446-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 67886. Variant chr3-38622446-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 67886. Variant chr3-38622446-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 67886. Variant chr3-38622446-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 67886. Variant chr3-38622446-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 67886. Variant chr3-38622446-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 67886.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2 link	c.436G>A	p.Val146Met	missense_variant	Exon 4 of 28	ENST00000413689.6	NP_001092874.1	Q14524H9KVD2
SCN5A	NM_000335.5 link	c.436G>A	p.Val146Met	missense_variant	Exon 4 of 28	ENST00000423572.7	NP_000326.2	Q14524-2Q86V90

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6 link	c.436G>A	p.Val146Met	missense_variant	Exon 4 of 28	5	NM_001099404.2	ENSP00000410257.1		H9KVD2
SCN5A	ENST00000423572.7 link	c.436G>A	p.Val146Met	missense_variant	Exon 4 of 28	1	NM_000335.5	ENSP00000398266.2		Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000122

AC:

AN:

246296

AF XY:

0.000157

show subpopulations

Gnomad AFR exome

AF:

0.0000656

Gnomad AMR exome

AF:

0.000643

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000559

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000268

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000295

AC:

AN:

1460014

Hom.:

Cov.:

AF XY:

0.0000317

AC XY:

AN XY:

726080

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33466

American (AMR)

AF:

0.000449

AC:

AN:

44542

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26100

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39670

South Asian (SAS)

AF:

0.0000584

AC:

AN:

85608

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53282

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00000900

AC:

AN:

1111252

Other (OTH)

AF:

0.0000663

AC:

AN:

60330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41448

American (AMR)

AF:

0.0000655

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00000656

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.000149

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cardiac arrhythmia

Uncertain:2

May 23, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces valine with methionine at codon 146 of the SCN5A protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual suspected to be affected with Brugada syndrome (PMID: 20129283) and in an individual affected with sudden cardiac arrest (PMID: 29884292). This variant has been identified in 30/246296 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The elevated variant allele frequency in the general population indicates that this variant may not be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Sep 23, 2024

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Uncertain:1Benign:1

Jan 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 04, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in a patient with clinically suspected Brugada syndrome in published literature (PMID: 20129283); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30203441, 30662450, 20129283) -

Brugada syndrome 1

Benign:1

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Sep 17, 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:20129283). 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

Benign

0.26

CardioboostArm

Uncertain

0.16

CardioboostCm

Uncertain

0.73

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.95

.;.;.;.;.;D;.;.;.;D

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.89

.;D;D;D;D;D;D;.;D;D

M_CAP

Pathogenic

0.80

MetaRNN

Pathogenic

0.76

D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.4

.;M;.;.;.;M;.;.;.;.

PhyloP100

3.1

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-2.4

N;N;N;N;N;N;N;N;N;.

REVEL

Pathogenic

0.78

Sift

Uncertain

0.0010

D;D;D;D;D;D;D;D;D;.

Sift4G

Uncertain

0.027

D;D;D;D;D;D;D;D;D;D

Polyphen

0.99

D;D;.;D;.;D;D;.;.;.

Vest4

0.89

MutPred

0.81

Loss of catalytic residue at V146 (P = 0.0407);Loss of catalytic residue at V146 (P = 0.0407);Loss of catalytic residue at V146 (P = 0.0407);Loss of catalytic residue at V146 (P = 0.0407);Loss of catalytic residue at V146 (P = 0.0407);Loss of catalytic residue at V146 (P = 0.0407);Loss of catalytic residue at V146 (P = 0.0407);Loss of catalytic residue at V146 (P = 0.0407);Loss of catalytic residue at V146 (P = 0.0407);Loss of catalytic residue at V146 (P = 0.0407);

MVP

0.98

MPC

1.1

ClinPred

0.26

GERP RS

4.0

Varity_R

0.44

gMVP

0.87

Mutation Taster

=0/100

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over