rs757532106

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5

The NM_001099404.2(SCN5A):c.5872C>T(p.Arg1958Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000329 in 1,608,582 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

SCN5A
NM_001099404.2 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:5

Conservation

PhyloP100: 3.08

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 7 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 8 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 3-38550500-G-A is Pathogenic according to our data. Variant chr3-38550500-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 201546.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=5, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2 linkuse as main transcript	c.5872C>T	p.Arg1958Ter	stop_gained	28/28	ENST00000413689.6
SCN5A	NM_000335.5 linkuse as main transcript	c.5869C>T	p.Arg1957Ter	stop_gained	28/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6 linkuse as main transcript	c.5872C>T	p.Arg1958Ter	stop_gained	28/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7 linkuse as main transcript	c.5869C>T	p.Arg1957Ter	stop_gained	28/28	1	NM_000335.5	A1	Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000449

AC:

AN:

245204

Hom.:

AF XY:

0.0000451

AC XY:

AN XY:

132946

show subpopulations

Gnomad AFR exome

AF:

0.0000652

Gnomad AMR exome

AF:

0.000146

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000667

Gnomad FIN exome

AF:

0.0000941

Gnomad NFE exome

AF:

0.00000901

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000316

AC:

AN:

1456370

Hom.:

Cov.:

AF XY:

0.0000415

AC XY:

AN XY:

723480

show subpopulations

Gnomad4 AFR exome

AF:

0.0000898

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000233

Gnomad4 FIN exome

AF:

0.000225

Gnomad4 NFE exome

AF:

0.0000199

Gnomad4 OTH exome

AF:

0.0000333

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000648

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000661

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 19, 2022	Reported in association with LQTS, borderline QTc intervals, idopathic arrhythmia, and DCM (Trolle et al., 2013; Chang et al., 2014; Walsh et al., 2017; Mellor et al., 2017); Nonsense variant predicted to result in protein truncation as the last 59 amino acids are lost, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 15840476, 27532257, 24388587, 19862833, 28600387, 33087929, 32533946, 31447099, 23936059) -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Oct 12, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 11, 2024	This sequence change creates a premature translational stop signal (p.Arg1958*) in the SCN5A gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 59 amino acid(s) of the SCN5A protein. This variant is present in population databases (rs757532106, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with clinical features of long QT syndrome, dilated cardiomyopathy or unexplained cardiac arrest (PMID: 15840476, 19862833, 24388587, 27532257, 28600387). ClinVar contains an entry for this variant (Variation ID: 201546). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal does not substantially affect SCN5A function (PMID: 32533946). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 21, 2018	- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 02, 2023

The p.R1958* variant (also known as c.5872C>T), located in coding exon 27 of the SCN5A gene, results from a C to T substitution at nucleotide position 5872. This changes the amino acid from an arginine to a stop codon within coding exon 27. This alteration has been reported in a long QT syndrome cohort, a dilated cardiomyopathy cohort, a Turner syndrome cohort, a hearing loss cohort, and a cardiac arrest survivor cohort (Hedley PL et al. Hum. Mutat. 2009;30:1486-511; Trolle C et al. PLoS ONE. 2013;8:e69614; Chang RK et al. J. Pediatr. 2014;164:590-5.e1-3; Mellor G et al. Circ Cardiovasc Genet. 2017;10:e001686; Walsh R et al. Genet. Med. 2017;19:192-203). This alteration has also been reported in biobank cohorts (Zouk et al. Am J Hum Genet, 2019 Sep;105:588-605; Van Hout CV et al. Nature, 2020 Oct;586:749-756). Premature stop codons are typically deleterious in nature, however, this stop codon occurs at the 3' terminus of SCN5A, is not expected to trigger nonsense-mediated mRNA decay, and removes only the last 59 amino acids of the protein. The exact functional impact of these removed amino acids is unknown at this time. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Cardiac arrhythmia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Dec 16, 2022

This c.5872C>T (p.Arg1958*) variant changes 1 nucleotide in exon 28 of the SCN5A gene, creating a premature translation stop signal. This variant is also described as c.5869C>T (p.Arg1957*) based on a different transcript NM_000335.5. This variant occurs in the last exon and is expected to result in a truncated protein product missing the last 59 amino acids of the protein. To our knowledge, functional studies have not been reported for this variant. However, a different truncation variant p.Arg1944* missing the last 73 amino acids of the protein has shown negligible effects on protein expression and function in an experimental study (PMID: 28370132) (ClinVar variation ID: 201596). This c.5872C>T (p.Arg1958*) variant has been reported in an individual affected with long QT syndrome (PMID: 19862833), in two individuals having borderline long QTc intervals (PMID: 23936059, 24388587), in two individuals with dilated cardiomyopathy (PMID: 27532257, 29961767) and in an individual with unexplained cardiac arrest (PMID: 28600387). This variant has also been identified in 13/276598 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.30

Cadd

Pathogenic

Dann

Uncertain

0.99

Eigen

Benign

0.13

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.37

MutationTaster

Benign

1.0

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

Vest4

0.85

GERP RS

4.1

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