rs370694515

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP2PP5

The NM_001099404.2(SCN5A):c.5693G>A(p.Arg1898His) variant causes a missense change. The variant allele was found at a frequency of 0.0000316 in 1,613,900 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R1898C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

SCN5A
NM_001099404.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:6

Conservation

PhyloP100: 6.15

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:

Genome browser will be placed here

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 10 pathogenic changes around while only 0 benign (100%) in NM_001099404.2

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant where missense usually causes diseases, SCN5A

PP5

Variant 3-38550679-C-T is Pathogenic according to our data. Variant chr3-38550679-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 207974.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=6, Pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2 linkuse as main transcript	c.5693G>A	p.Arg1898His	missense_variant	28/28	ENST00000413689.6
SCN5A	NM_000335.5 linkuse as main transcript	c.5690G>A	p.Arg1897His	missense_variant	28/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6 linkuse as main transcript	c.5693G>A	p.Arg1898His	missense_variant	28/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7 linkuse as main transcript	c.5690G>A	p.Arg1897His	missense_variant	28/28	1	NM_000335.5	A1	Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000441

AC:

AN:

249288

Hom.:

AF XY:

0.0000518

AC XY:

AN XY:

135230

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000229

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000308

AC:

AN:

1461672

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

727114

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000162

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000180

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000827

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000235

AC:

ESP6500EA

AF:

0.000119

AC:

ExAC

AF:

0.0000661

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 17, 2019	Identified in a patient with DCM and a patient with clinical features suggestive of ARVC in the published literature (Haas et al., 2015; Te Riele et al., 2017); Functional studies in patient derived cells suggest this variant leads to a reduction in both peak sodium current and channel clusters at intercalated discs (Te Riele et al., 2017). However, further functional studies are needed to clarify the role of this variant in human disease.; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar as a variant of uncertain significance by other clinical laboratories (ClinVar Variant ID 207974; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 25904541, 31336969, 28069705, 25163546, 29845439, 30205876, 30302938) -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1898 of the SCN5A protein (p.Arg1898His). This variant is present in population databases (rs370694515, gnomAD 0.02%). This missense change has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy, and/or long QT Syndrome (PMID: 25163546, 28069705, 34755423, 36303204). This variant is also known as c.G5639A, p.R1880H. ClinVar contains an entry for this variant (Variation ID: 207974). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SCN5A function (PMID: 28069705). This variant disrupts the p.Arg1898 amino acid residue in SCN5A. Other variant(s) that disrupt this residue have been observed in individuals with SCN5A-related conditions (PMID: 26173111), which suggests that this may be a clinically significant amino acid residue. 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 01, 2023	This missense variant replaces arginine with histidine at codon 1898 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). Experimental functional studies have shown that this variant reduces sodium current and may disrupt formation of a functional complex with cell adhesion molecules (PMID: 28069705). This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 25163546), arrhythmogenic right ventricular cardiomyopathy (PMID: 28069705), and flu myocarditis (PMID: 30084490). This variant has also been identified in 12/280694 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	Jan 11, 2024	This missense variant replaces arginine with histidine at codon 1898 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). Experimental functional studies have shown that this variant reduces sodium current and may disrupt formation of a functional complex with cell adhesion molecules (PMID: 28069705). This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 25163546), arrhythmogenic right ventricular cardiomyopathy (PMID: 28069705), and flu myocarditis (PMID: 30084490). This variant has also been identified in 12/280694 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. -

Long QT syndrome 3

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital

Jan 01, 2014

- -

Familial isolated arrhythmogenic right ventricular dysplasia

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 06, 2019

The p.Arg1898His variant in SCN5A has been reported in one patient with DCM (Haas 2015) and in one patient with clinical features suggestive of arrhythmogenic right ventricular cardiomyopathy (ARVC) (Te Riele 2017) and also in 1 individual with left ventricular non compaction with segmental hypertrophy (LMM data). It is also present in ClinVar (ID 207974). It has been identified in 7/30602 South Asian chromosomes by the gnomAD. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Arg1898His variant is uncertain. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 17, 2023

The p.R1898H variant (also known as c.5693G>A), located in coding exon 27 of the SCN5A gene, results from a G to A substitution at nucleotide position 5693. The arginine at codon 1898 is replaced by histidine, an amino acid with highly similar properties. This alteration has been detected in a dilated cardiomyopathy cohort, in an individual with confirmed myocarditis, and an individual with features of arrhythmogenic right ventricular cardiomyopathy (Haas J et al. Eur. Heart J., 2015;36:1123-35a; Te Riele AS et al. Cardiovasc. Res., 2017;113:102-111; Nelson McMillan K. Artif Organs. 2019;43(1):21-29). This variant (referred to as p.R1865H) co-occurred with a de novo KCNH2 variant in an individual with overlapped phenotypes of LQTS and sinoatrial node dysfunction, while two reportedly unaffected relatives also had this SCN5A variant (Yang Z et al. Ann Noninvasive Electrocardiol. 2022 Jan;27(1):e12889). This variant has also been detected in a self-reported healthy cohort; however, details were limited (Bajaj A et al. Hum Genomics. 2022 Aug;16(1):30). One study indicated this alteration may have an impact on sodium channel function (Te Riele AS et al. Cardiovasc. Res., 2017;113:102-111). 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

Benign

0.20

CardioboostArm

Uncertain

0.75

CardioboostCm

Uncertain

0.28

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Pathogenic

0.23

Cadd

Uncertain

Dann

Pathogenic

1.0

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.98

M_CAP

Pathogenic

0.54

MetaRNN

Uncertain

0.73

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

MetaSVM

Pathogenic

1.1

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-3.2

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

REVEL

Pathogenic

0.80

Sift

Benign

0.042

D;D;D;D;T;D;D;T;T

Sift4G

Benign

0.071

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

Polyphen

0.63

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

Vest4

0.69

MVP

0.89

MPC

1.6

ClinPred

0.57

GERP RS

4.9

Varity_R

0.55

gMVP

0.92

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.

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