Variant rs373118001 details in Genebe, Genetics Data Aggregator

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a region_of_interest Interaction with FGF13 (size 62) in uniprot entity SCN5A_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000335.5

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SCN5A. . Gene score misZ 2.7504 (greater than the threshold 3.09). Trascript score misZ 4.8279 (greater than threshold 3.09). GenCC has associacion of gene with progressive familial heart block, type 1A, Brugada syndrome, familial sick sinus syndrome, short QT syndrome, paroxysmal familial ventricular fibrillation, progressive familial heart block, long QT syndrome 3, familial atrial fibrillation, catecholaminergic polymorphic ventricular tachycardia, dilated cardiomyopathy, dilated cardiomyopathy 1E, arrhythmogenic right ventricular cardiomyopathy, Brugada syndrome 1, atrial standstill, familial isolated dilated cardiomyopathy, familial long QT syndrome, sick sinus syndrome 1.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.78

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2 linkuse as main transcript	c.5692C>T	p.Arg1898Cys	missense_variant	28/28	ENST00000413689.6	NP_001092874.1	Q14524H9KVD2
SCN5A	NM_000335.5 linkuse as main transcript	c.5689C>T	p.Arg1897Cys	missense_variant	28/28	ENST00000423572.7	NP_000326.2	Q14524-2Q86V90

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6 linkuse as main transcript	c.5692C>T	p.Arg1898Cys	missense_variant	28/28	5	NM_001099404.2	ENSP00000410257.1		H9KVD2
SCN5A	ENST00000423572.7 linkuse as main transcript	c.5689C>T	p.Arg1897Cys	missense_variant	28/28	1	NM_000335.5	ENSP00000398266.2		Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

10

AN:

152208

Hom.:

0

Cov.:

33

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000387

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000321

AC:

8

AN:

249288

Hom.:

0

AF XY:

0.0000370

AC XY:

5

AN XY:

135232

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000556

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000531

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000308

AC:

45

AN:

1461660

Hom.:

0

Cov.:

32

AF XY:

0.0000275

AC XY:

20

AN XY:

727104

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000297

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.0000656

AC:

10

AN:

152326

Hom.:

0

Cov.:

33

AF XY:

0.0000940

AC XY:

7

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000388

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000114

Hom.:

0

Bravo

AF:

0.0000340

ESP6500AA

AF:

0.00

AC:

0

ESP6500EA

AF:

0.000119

AC:

1

ExAC

AF:

0.0000248

AC:

3

Asia WGS

AF:

0.000289

AC:

1

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 19, 2024	Reported in patients with clinically diagnosed Brugada syndrome, some of whom harbored additional cardiogenetic variants (PMID: 26173111, 27707468, 29306897, 25904541); Published functional studies suggest a damaging effect (PMID: 32533946); 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: 25904541, 27707468, 30662450, 34426522, 32880476, 30847666, 26746457, 30203441, 34621001, 26173111, 29306897, 29447731, 32533946) -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Brugada syndrome 1

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Cardiac arrhythmia

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 27, 2023	This missense variant replaces arginine with cysteine at codon 1898 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). A functional study has shown that this variant had 28% of the peak current density compared to wild type (PMID: 32533946). This variant has been reported in two individuals affected with Brugada syndrome (PMID: 26173111, 29306897). One of these individuals carried a pathogenic truncation variant in the same gene that could explain the observed phenotype. This variant has also been reported in an individual affected with noncompaction cardiomyopathy (PMID: 29447731). This variant has been identified in 10/280692 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 01, 2023	This missense variant replaces arginine with cysteine at codon 1898 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). A functional study has shown that the variant protein exhibit 28% of the peak current density compared to wild type protein (PMID: 32533946). This variant has been reported in two individuals affected with Brugada syndrome (PMID: 26173111, 29306897). One of these individuals carried a pathogenic truncation variant in the same gene that could explain the observed phenotype. This variant has also been reported in an individual affected with noncompaction cardiomyopathy (PMID: 29447731). This variant has been identified in 10/280692 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

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 09, 2023

Variant summary: SCN5A c.5692C>T (p.Arg1898Cys) results in a non-conservative amino acid change in 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 3.2e-05 in 249288 control chromosomes (gnomAD). The variant, c.5692C>T, has been reported in the literature in at least two individuals affected with Brugada syndrome, however one of these patient also carried a potentially pathogenic SCN5A variant (Selga_2015, Zhang_2016, Huang_2018). In addition, the variant has been reported in at least two patients affected with noncompaction cardiomyopathy and dilated cardiomyopathy, however without strong evidence for causality (van Waning_2018, van Lint_2019, Verdonschot_2020). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function, and demonstrated a reduced ion channel current, indicating a partial loss of function for the variant protein (Glazer_2020). The following publications have been ascertained in the context of this evaluation (PMID: 32533946, 26173111, 25904541, 27707468, 29306897, 29447731, 30847666, 32880476). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Ventricular fibrillation, paroxysmal familial, type 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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. -

Dilated cardiomyopathy 1E

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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. -

Brugada syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 01, 2022

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1898 of the SCN5A protein (p.Arg1898Cys). This variant is present in population databases (rs373118001, gnomAD 0.006%). This missense change has been observed in individual(s) with Brugada syndrome and/or dilated cardiomyopathy (PMID: 26173111, 29306897, 30847666, 32880476). ClinVar contains an entry for this variant (Variation ID: 518750). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 32533946) indicates that this missense variant is expected to disrupt SCN5A function. 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. -

Sick sinus syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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. -

Progressive familial heart block, type 1A

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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. -

Long QT syndrome 3

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 23, 2023

The p.R1898C variant (also known as c.5692C>T), located in coding exon 27 of the SCN5A gene, results from a C to T substitution at nucleotide position 5692. The arginine at codon 1898 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in Brugada syndrome and sudden unexplained nocturnal death cohorts; however, clinical details were limited and the sudden death case also had a second SCN5A variant detected (Selga E et al. PLoS ONE, 2015 Jul;10:e0132888; Zhang L et al. Mayo Clin. Proc., 2016 Nov;91:1503-1514). This variant has also been detected in individuals reported to have dilated cardiomyopathy or noncompaction cardiomyopathy; however, clinical details were limited and some reports may overlap (van Waning JI et al. J Am Coll Cardiol. 2018 Feb;71(7):711-722; van Lint FHM et al. Neth Heart J. 2019 Jun;27(6):304-309; Verdonschot JAJ et al. Circ Genom Precis Med. 2020 Oct;13(5):476-487). In addition, this variant has been detected in cohorts not selected for the presence of cardiovascular disease; however, details were limited (Chetruengchai W et al. J Hum Genet. 2022 Mar;67(3):137-142; Kars ME et al. Proc Natl Acad Sci U S A. 2021 Sep;118(36)). Functional studies suggest this variant may result in reduced ion channel current; however, additional evidence is needed to confirm this finding (Glazer AM et al. Am J Hum Genet. 2020 Jul;107(1):111-123).This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

CardioboostCm

Uncertain

0.24

BayesDel_addAF

Pathogenic

0.30

D

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

29

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.86

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

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Pathogenic

0.98

D

LIST_S2

Uncertain

0.93

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

M_CAP

Pathogenic

0.68

D

MetaRNN

Pathogenic

0.78

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

MetaSVM

Pathogenic

1.1

D

MutationAssessor

Pathogenic

3.1

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

PrimateAI

Pathogenic

0.80

T

PROVEAN

Pathogenic

-5.7

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

REVEL

Pathogenic

0.81

Sift

Uncertain

0.020

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

Sift4G

Uncertain

0.0090

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

Polyphen

0.37

B;B;.;B;.;D;D;.;.

Vest4

0.88

MVP

0.81

MPC

1.7

ClinPred

0.82

D

GERP RS

4.0

Varity_R

0.68

gMVP

0.95

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.

rs373118001

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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