Variant rs199473286 details in Genebe, Genetics Data Aggregator

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in ENST00000423572.7

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-38551478-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 242199.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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, 0.993

PP5

Variant 3-38551477-C-T is Pathogenic according to our data. Variant chr3-38551477-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67939.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=6, Pathogenic=3, Uncertain_significance=1, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2 linkuse as main transcript	c.4895G>A	p.Arg1632His	missense_variant	28/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5 linkuse as main transcript	c.4892G>A	p.Arg1631His	missense_variant	28/28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6 linkuse as main transcript	c.4895G>A	p.Arg1632His	missense_variant	28/28	5	NM_001099404.2	ENSP00000410257	P4
SCN5A	ENST00000423572.7 linkuse as main transcript	c.4892G>A	p.Arg1631His	missense_variant	28/28	1	NM_000335.5	ENSP00000398266	A1	Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

1

AN:

152066

Hom.:

0

Cov.:

31

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

2

AN:

251374

Hom.:

0

AF XY:

0.00

AC XY:

0

AN XY:

135856

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

12

AN:

1461798

Hom.:

0

Cov.:

35

AF XY:

0.00000688

AC XY:

5

AN XY:

727188

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

1

AN:

152066

Hom.:

0

Cov.:

31

AF XY:

0.0000135

AC XY:

1

AN XY:

74264

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9Uncertain:1Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 30, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 18, 2023	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1632 of the SCN5A protein (p.Arg1632His). This variant is present in population databases (rs199473286, gnomAD 0.003%). This missense change has been observed in individuals with Brugada syndrome or sick sinus syndrome (PMID: 14523039, 24948852, 28781330, 34539730, 35027292, 35124229). ClinVar contains an entry for this variant (Variation ID: 67939). 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. Experimental studies have shown that this missense change affects SCN5A function (PMID: 20384651, 20539757, 32533946). This variant disrupts the p.Arg1632 amino acid residue in SCN5A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26031372, 27082542, 31191357). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 21, 2022	Observed in the heterozygous state in patients with Brugada syndrome and in the compound heterozygous state with a second SCN5A variant in patients with sick sinus syndrome, and segregated with SCN5A-related phenotypes in relatives from unrelated families in the published literature (Benson et al., 2003; van Malderen et al., 2017; Robyns et al., 2014; Robyns et al., 2018; Liu et al., 2021); Published functional studies demonstrate a damaging effect on channel kinetics (Benson et al., 2003; Gui et al., 2010); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27381756, 20384651, 25863800, 20539757, 28018021, 17368591, 31521807, 32850980, 31447099, 33131149, 29709101, 29728395, 24948852, 28781330, 26582918, 14523039, 34539730) -

Brugada syndrome 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Clinical Genomics Laboratory, Washington University in St. Louis

Aug 29, 2023

The SCN5A c.4892G>A (p.Arg1631His) variant, also published as Arg1632His, has been reported in at least four individuals and families affected with sick sinus syndrome or Brugada syndrome (Benson DW et al., PMID: 14523039; Liu Y et al., PMID: 34539730; Robyns T et al., PMID: 24948852; Van Malderen SCH et al., PMID: 28781330). This variant has been reported in the ClinVar database as a germline pathogenic variant by one submitter, a likely pathogenic variant by five submitters, and a variant of uncertain significance by one submitter. Computational predictors indicate that the variant is damaging, evidence that correlates with impact to SCN5A function. In support of this prediction, functional studies have shown this variant effects cardiac sodium channel kinetics (Glazer AM et al., PMID: 32533946; Gui J et al., PMID: 20384651; Gui J et al., PMID: 20539757). Another variant in the same codon, p.Arg1631Cys, has also been reported in affected individuals (García-Molina E at al., PMID: 27082542; Nakajima T et al., PMID: 26031372). This variant is only observed on 2/251,374 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic. -

Sick sinus syndrome 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital

Feb 28, 2020

- -

Brugada syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Feb 05, 2024

This missense variant replaces arginine with histidine at codon 1632 of the SCN5A protein. This variant is also known as p.Arg1631His in the literature based on a different NM_000335 transcript. This variant is found within a highly conserved region (a.a.1530-1771) in the transmembrane domain DIV. Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with Brugada syndrome (PMID: 32893267). In vitro functional studies have shown that this variant leads to profound impairment in channel function (PMID: 14523039, 20539757, 32533946). This variant has been reported in at least eight individuals affected with Brugada syndrome from five families (PMID: 24948852, 28781330, 29709101, 32893267, 37061847), in two young individuals affected with sick sinus syndrome, one of which was compound heterozygous for this variant and another pathogenic variant (PMID: 14523039, 34539730), and in two infants affected with sudden unexpected death (PMID: 35027292, Clinvar SCV002030070.1). It has been shown that this variant segregates with SCN5A-related phenotypes in one of the families including four carriers who were affected with Brugada syndrome, sick sinus syndrome, or progressive familial heart block (PMID: 24948852). This variant has been identified in 2/251374 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg1632Cys, is known to be pathogenic (Clinvar variation ID 242199), indicating that arginine at this position is important for SCN5A protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 08, 2023

The p.R1632H variant (also known as c.4895G>A), located in coding exon 27 of the SCN5A gene, results from a G to A substitution at nucleotide position 4895. The arginine at codon 1632 is replaced by histidine, an amino acid with highly similar properties, and is located in the DIV-S4 transmembrane region. This alteration has been reported in multiple probands with SCN5A-related arrhythmia including sick sinus syndrome and Brugada syndrome (Benson DW et al. J. Clin. Invest. 2003;112:1019-28; Robyns T et al. Indian Pacing Electrophysiol J. 2014;14:133-49; Van Malderen SCH et al. Circ. J. 2017;82:53-61; Liu Y et al. Front Genet. 2021 Sep;12:677699; Ambry internal data). Functional studies suggest this alteration impairs recovery from inactivation and current density; however, the physiological relevance of these results is unclear (Benson DW et al. J. Clin. Invest. 2003;112:1019-28; Gui J et al. PLoS ONE. 2010;5:e10985; Glazer AM et al. Am. J. Hum. Genet. 2020 Jul;107(1):111-123). In addition, a deep mutational scanning study categorized this alteration as a possible loss of function alteration (Glazer AM et al. Circ Genom Precis Med, 2020 02;13:e002786). Based on internal structural analysis, the arginine impacted by this alteration is part of a highly conserved set of residues that generate a characteristic motif necessary to the function of voltage-sensing channels, and this variant is predicted to disrupt voltage gating activity (Gandhi CS et al. J. Gen. Physiol., 2002 Oct;120:455-63; Starace DM et al. Nature, 2004 Feb;427:548-53; DeCaen PG et al. Proc Natl Acad Sci U S A. 2008 Sep;105(39):15142-7; Ambry internal data). In addition, other variants affecting this codon (p.R1632L, c.4895G>T and p.R1632C, c.4894C>T) have been reported in association with Brugada syndrome (Batchvarov VN et al. J Electrocardiol;44:308; Nakajima T et al. Heart Rhythm. 2015 Nov;12(11):2296-304; Van Malderen SCH et al. Circ. J. 2017;82:53-61). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Long QT syndrome 3;C4551804:Brugada syndrome 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Aug 22, 2018

This c.4895G>A (p.Arg1632His) variant in exon 28 of the SCN5A gene results in an amino acid change at residue 1632 of an arginine to a histidine. This variant has been observed in patients with sick sinus syndrome and Brugada syndrome (PMID: 14523039, 24948852) and is rarely observed in general population databases. Functional studies have shown a strong effect on cardiac sodium channel kinetics (PMID: 20539757). Therefore, the c.4895G>A (p.Arg1632His) variant in the SCN5A gene is classified as likely pathogenic. -

Cardiac arrhythmia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Sep 18, 2023

This missense variant replaces arginine with histidine at codon 1632 of the SCN5A protein. This variant is also known as p.Arg1631His in the literature based on a different NM_000335 transcript. This variant is found within a highly conserved region (a.a.1530-1771) in the transmembrane domain DIV. Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with Brugada syndrome (PMID: 32893267). In vitro functional studies have shown that this variant leads to profound impairment in channel function (PMID: 14523039, 20539757, 32533946). This variant has been reported in at least eight individuals affected with Brugada syndrome from five families (PMID: 24948852, 28781330, 29709101, 32893267, 37061847), in two young individuals affected with sick sinus syndrome, one of which was compound heterozygous for this variant and another pathogenic variant (PMID: 14523039, 34539730), and in two infants affected with sudden unexpected death (PMID: 35027292, Clinvar SCV002030070.1). It has been shown that this variant segregates with SCN5A-related phenotypes in one of the families including four carriers who were affected with Brugada syndrome, sick sinus syndrome, or progressive familial heart block (PMID: 24948852). This variant has been identified in 2/251374 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg1632Cys, is known to be pathogenic (Clinvar variation ID 242199), indicating that arginine at this position is important for SCN5A protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. -

SUDDEN INFANT DEATH SYNDROME

Uncertain:1

Uncertain significance, flagged submission

research

Robert's Program, Boston Children's Hospital

Oct 01, 2021

We classify this variant as a variant of uncertain significance using ACMG/AMP criteria. As this variant has functional evidence supporting pathogenicty, we suspect this variant is favoring pathogenic. -

Conduction system disorder

Other:1

not provided, no classification provided

literature only

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

-

This variant has been reported in the following publications (PMID:14523039;PMID:20384651;PMID:20539757). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

CardioboostCm

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.50

D

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

30

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

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

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Uncertain

0.96

D

LIST_S2

Uncertain

0.92

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

M_CAP

Pathogenic

0.97

D

MetaRNN

Pathogenic

0.99

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

MetaSVM

Pathogenic

0.95

D

MutationAssessor

Pathogenic

3.6

.;.;.;.;.;H;.;.;.

MutationTaster

Benign

1.0

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

PrimateAI

Pathogenic

0.84

D

PROVEAN

Pathogenic

-4.6

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

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

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

Sift4G

Benign

0.083

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

Polyphen

1.0

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

Vest4

0.97

MutPred

0.98

.;.;Gain of methylation at R1629 (P = 0.0457);.;.;Gain of methylation at R1629 (P = 0.0457);.;.;.;

MVP

0.99

MPC

1.6

ClinPred

1.0

D

GERP RS

4.5

Varity_R

0.88

gMVP

1.0

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.

rs199473286

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over