3-38620885-C-T

Position:

chr3-38620885-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP2PP3_Strong

The NM_000335.5(SCN5A):c.569G>A(p.Arg190Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,610,190 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

SCN5A
NM_000335.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:9O:1

Conservation

PhyloP100: 7.90

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 links:

SCN5A (HGNC:):

SCN5A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

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, 0.984

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2 linkuse as main transcript	c.569G>A	p.Arg190Gln	missense_variant	5/28	ENST00000413689.6	NP_001092874.1	Q14524H9KVD2
SCN5A	NM_000335.5 linkuse as main transcript	c.569G>A	p.Arg190Gln	missense_variant	5/28	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.569G>A	p.Arg190Gln	missense_variant	5/28	5	NM_001099404.2	ENSP00000410257.1		H9KVD2
SCN5A	ENST00000423572.7 linkuse as main transcript	c.569G>A	p.Arg190Gln	missense_variant	5/28	1	NM_000335.5	ENSP00000398266.2		Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152202

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:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000538

AC:

AN:

241822

Hom.:

AF XY:

0.0000533

AC XY:

AN XY:

131244

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000344

Gnomad SAS exome

AF:

0.0000337

Gnomad FIN exome

AF:

0.0000472

Gnomad NFE exome

AF:

0.0000367

Gnomad OTH exome

AF:

0.000169

GnomAD4 exome

AF:

0.0000336

AC:

AN:

1457988

Hom.:

Cov.:

AF XY:

0.0000372

AC XY:

AN XY:

724892

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000227

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000758

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.0000351

Gnomad4 OTH exome

AF:

0.0000498

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000577

Hom.:

Bravo

AF:

0.0000264

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000662

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 31, 2018	The R190Q variant of uncertain significance in the SCN5A gene has been reported in a patient suspected to have Brugada syndrome, as well as several patients suspected of having long QT syndrome (Chung et al., 2007; Ogowa et al., 2010; Reithmann et al., 2012; Anderson et al., 2017). However, LQTS is caused by gain of function variants in the SCN5A channel (NaV1.5), while Brugada syndrome is caused by loss of function variants. As this variant has been identified in individuals evaluated for diseases that have different mechanisms of pathogenicity, its clinical significance is uncertain. Furthermore, functional studies do not demonstrate a deleterious effect (Kapplinger et al., 2015; Anderson et al., 2017). The R190Q variant is observed 12/270132 (0.004%) alleles from individuals of multiple ethnic backgrounds in large population cohorts (Lek et al., 2016). Nevertheless, the R190Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 02, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 190 of the SCN5A protein (p.Arg190Gln). This variant is present in population databases (rs199473069, gnomAD 0.03%). This missense change has been observed in individual(s) with long QT (LQT) syndrome, prolonged QT, Brugada syndrome, sudden death, or dilated cardiomyopathy (PMID: 17905336, 20137763, 21908450, 27930701, 28412158, 32746448). ClinVar contains an entry for this variant (Variation ID: 68005). 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. -

Cardiac arrhythmia

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 09, 2023	This missense variant replaces arginine with glutamine at codon 190 of the SCN5A protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. An experimental study has shown that the mutant protein shows normal electrophysiological function in a cell-based assay (PMID: 25904541). This variant has been reported in at least two unrelated individuals affected with long QT syndrome (PMID: 17905336, 21908450, 32893267), in three individuals suspected of having Brugada syndrome (PMID: 20137763) or long QT syndrome (PMID: 28412158). This variant has also been reported in an individual with sudden unexplained death and suspected hypertrophic cardiomyopathy (PMID: 27930701), pediatric dilated cardiomyopathy (PMID: 32746448), or drug-induced long QT syndrome (PMID: 35113648). This variant has also been identified in 14/273216 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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	Jan 11, 2024	This missense variant replaces arginine with glutamine at codon 190 of the SCN5A protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. An experimental study has shown that the mutant protein shows normal electrophysiological function in a cell-based assay (PMID: 25904541). This variant has been reported in at least two unrelated individuals affected with long QT syndrome (PMID: 17905336, 21908450, 32893267), in three individuals suspected of having Brugada syndrome (PMID: 20137763) or long QT syndrome (PMID: 28412158). This variant has also been reported in an individual with sudden unexplained death and suspected hypertrophic cardiomyopathy (PMID: 27930701), pediatric dilated cardiomyopathy (PMID: 32746448), or drug-induced long QT syndrome (PMID: 35113648). This variant has also been identified in 14/273216 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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

Jun 21, 2022

Variant summary: SCN5A c.569G>A (p.Arg190Gln) results in a conservative amino acid change located in the Ion transport domain (IPR005821) of 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 5.4e-05 in 241822 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in SCN5A causing Arrhythmia (5.4e-05 vs 0.0001), allowing no conclusion about variant significance. c.569G>A has been reported in the literature in individuals affected with long QT (LQT) syndrome, prolonged QT, or Brugada syndrome (examples:Chung_2007, Ogawa_2010, Reithmann_2011, Sanchez_2016, Anderson_2017, Kroncke_2018 and Burstein_2021). Multiple authors in these publications have classified the variant benign and VUS. Using in-vitro and in silico tools Kapplinger_2016 have suggested a benign role for this variant. These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Brugada syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

SUDDEN INFANT DEATH SYNDROME;C1832680:Dilated cardiomyopathy 1E;C1837845:Sick sinus syndrome 1;C1859062:Long QT syndrome 3;C1879286:Progressive familial heart block, type 1A;C2751898:Ventricular fibrillation, paroxysmal familial, type 1;C3151464:Atrial fibrillation, familial, 10;C4551804:Brugada syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 16, 2021

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 01, 2023

The p.R190Q variant (also known as c.569G>A), located in coding exon 4 of the SCN5A gene, results from a G to A substitution at nucleotide position 569. The arginine at codon 190 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in individuals with concerns for long QT syndrome (LQTS) (Chung SK et al. Heart Rhythm, 2007 Oct;4:1306-14; Reithmann C et al. Europace, 2012 Feb;14:299-300). Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). 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 conflicting at this time, the clinical significance of this alteration remains unclear. -

Long QT syndrome 3

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Jun 03, 2021

- -

Congenital long QT syndrome

Other:1

not provided, no classification provided

literature only

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

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:17905336). 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

0.24

CardioboostCm

Uncertain

0.86

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.97

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

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

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

M_CAP

Pathogenic

0.91

MetaRNN

Pathogenic

0.98

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.9

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

PrimateAI

Pathogenic

0.79

PROVEAN

Uncertain

-3.9

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

REVEL

Pathogenic

0.95

Sift

Uncertain

0.023

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

Sift4G

Uncertain

0.0040

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

Polyphen

1.0

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

Vest4

0.99

MutPred

0.95

Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);

MVP

0.98

MPC

1.2

ClinPred

0.77

GERP RS

4.1

Varity_R

0.85

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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.

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