rs727503408

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM5BP4

The NM_001099404.2(SCN5A):c.2990C>A(p.Ala997Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,610,176 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A997T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 1 hom. )

Consequence

SCN5A
NM_001099404.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 1.10

Publications

4 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 1 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-38581170-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 9388.

BP4

Computational evidence support a benign effect (MetaRNN=0.26543102).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2 link	c.2990C>A	p.Ala997Asp	missense_variant	Exon 17 of 28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5 link	c.2990C>A	p.Ala997Asp	missense_variant	Exon 17 of 28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6 link	c.2990C>A	p.Ala997Asp	missense_variant	Exon 17 of 28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7 link	c.2990C>A	p.Ala997Asp	missense_variant	Exon 17 of 28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes

AF:

0.00000661

AC:

AN:

151262

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000209

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000417

AC:

AN:

240014

AF XY:

0.0000533

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000170

GnomAD4 exome

AF:

0.0000233

AC:

AN:

1458914

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

725602

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33452

American (AMR)

AF:

0.00

AC:

AN:

44418

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26042

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39616

South Asian (SAS)

AF:

0.000326

AC:

AN:

85928

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52764

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1110716

Other (OTH)

AF:

0.0000332

AC:

AN:

60220

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

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:

0.00000661

AC:

AN:

151262

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73836

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41110

American (AMR)

AF:

0.00

AC:

AN:

15032

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.000209

AC:

AN:

4782

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10526

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67864

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.725

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:

0.00

Hom.:

ExAC

AF:

0.0000249

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Nov 14, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 997 of the SCN5A protein (p.Ala997Asp). This variant is present in population databases (rs727503408, gnomAD 0.03%). This missense change has been observed in individual(s) with sudden infant death (PMID: 24631775). ClinVar contains an entry for this variant (Variation ID: 165149). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Mar 25, 2016

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The A997D variant was reported in a 4 week old male with autopsy-negative sudden unexplained death and was called a class 3 variant which may or may not be causative" (Wang et al., 2014); however familial segregation information, in vitro functional studies and additional clinical information was not included. In addition, the A997D variant has been classified as a variant of uncertain significance by another clinical laboratory in ClinVar (Landrum et al., 2014). The A997D variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The A997D variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Nevertheless, this substitution occurs at a position that is not conserved across species and in silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign." -

Cardiac arrhythmia

Uncertain:2

May 01, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces alanine with aspartic acid at codon 997 of the SCN5A protein. Computational prediction suggests that this variant may have 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 affected with sudden death (PMID: 24631775), and in a healthy individuasl (PMID: 31983221). This variant has been identified in 10/240014 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Jan 10, 2023

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces alanine with aspartic acid at codon 997 of the SCN5A protein. Computational prediction suggests that this variant may have 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 affected with sudden death (PMID: 24631775). This variant has been identified in 10/240014 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1

Sep 09, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant classified as Uncertain Significance - Favor Benign. The p.Ala997Asp variant in SCN5A has been identified in one individual with a sudden unexplained death (Wang 2014 PMID: 2463177). It has also been reported by other clinical laboratories in ClinVar (Variation ID 165149) and has been identified in 0.03% (9/30136) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of this variant is uncertain, its frequency suggests that it is more likely to be benign. ACMG/AMP Criteria applied: BP4. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

CardioboostArm

Benign

0.00068

CardioboostCm

Benign

0.00096

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Benign

0.69

DEOGEN2

Benign

0.35

.;.;.;.;.;T;.;.;.

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.86

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

M_CAP

Pathogenic

0.71

MetaRNN

Benign

0.27

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.69

MutationAssessor

Benign

0.0

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

PhyloP100

1.1

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.12

N;N;N;N;N;N;N;N;N

REVEL

Pathogenic

0.74

Sift

Benign

0.37

T;T;T;T;T;T;T;T;T

Sift4G

Benign

0.64

T;T;T;T;T;T;T;T;T

Polyphen

0.062

B;B;.;B;.;B;B;.;.

Vest4

0.26

MutPred

0.55

Loss of glycosylation at P992 (P = 0.0954);Loss of glycosylation at P992 (P = 0.0954);Loss of glycosylation at P992 (P = 0.0954);Loss of glycosylation at P992 (P = 0.0954);Loss of glycosylation at P992 (P = 0.0954);Loss of glycosylation at P992 (P = 0.0954);Loss of glycosylation at P992 (P = 0.0954);Loss of glycosylation at P992 (P = 0.0954);Loss of glycosylation at P992 (P = 0.0954);

MVP

0.51

MPC

0.042

ClinPred

0.047

GERP RS

4.5

Varity_R

0.13

gMVP

0.61

Mutation Taster

=1/99

disease causing

(source)

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

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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