rs1060499900

Positions:

chr3-38551304-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP2PP3_Moderate

The NM_001099404.2(SCN5A):c.5068G>A(p.Asp1690Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,936 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 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

SCN5A
NM_001099404.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:7

Conservation

PhyloP100: 7.89

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.

PM1

In a topological_domain Extracellular (size 21) in uniprot entity SCN5A_HUMAN there are 5 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 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 4.7729 (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, 0.927

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2 linkuse as main transcript	c.5068G>A	p.Asp1690Asn	missense_variant	28/28	ENST00000413689.6
SCN5A	NM_000335.5 linkuse as main transcript	c.5065G>A	p.Asp1689Asn	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.5068G>A	p.Asp1690Asn	missense_variant	28/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7 linkuse as main transcript	c.5065G>A	p.Asp1689Asn	missense_variant	28/28	1	NM_000335.5	A1	Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152046

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251488

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

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:

0.00000684

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152046

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74242

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Functional study suggests pathogenicity, but no segs and only 1 proband; Absent from ExAC -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 20, 2023	Variant summary: SCN5A c.5068G>A (p.Asp1690Asn) results in a 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 4e-06 in 251488 control chromosomes. c.5068G>A has been reported in the literature in individuals affected with Brugada Syndrome (e.g. Nunez_2013). In one family, this variant does not co-segregate with Brugada Syndrome (Zeng_2016). Co-occurrence with a pathogenic variant has been reported (TTN c.48868C>T, p.Arg16290X, internal database), providing supporting evidence for a benign role. Three publications report experimental evidence evaluating an impact on protein function and showed that this variant affect SCN5A function (Nunez_2013, Zeng_2016), however, this effect may not associate with BrS clinical phenotype (Pearman_2020). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS. -

Cardiac arrhythmia

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 24, 2023	This missense variant replaces aspartic acid with asparagine at codon 1690 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). Functional studies have shown that this variant causes reduced channel trafficking to the plasma membrane, decreased sodium channel current density, positive shift of activation, and slower recovery from inactivation (PMID: 23085483, 23085483, 30232268). This variant has been reported in at least three unrelated individuals affected with Brugada syndrome (PMID: 23085483, 26173111, 27108952, 32268277, 32893267). One of these individuals carried a pathogenic c.3840+1G>A variant in the same gene that could explain the observed phenotype (PMID: 26173111). This variant has been identified in 1/251488 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	Apr 10, 2023	This missense variant replaces aspartic acid with asparagine at codon 1690 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). Functional studies have shown that this variant causes reduced channel trafficking to the plasma membrane, decreased sodium channel current density, positive shift of activation, and slower recovery from inactivation (PMID: 23085483, 23085483, 30232268). This variant has been reported in at least three unrelated individuals affected with Brugada syndrome (PMID: 23085483, 26173111, 27108952, 32268277, 32893267). One of these individuals carried a pathogenic c.3840+1G>A variant in the same gene that could explain the observed phenotype (PMID: 26173111). This variant has been identified in 1/251488 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. -

Brugada syndrome 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Immunology and Genetics Kaiserslautern

Jan 31, 2024

ACMG Criteria: PS3, PM1, PP3, PP5; Variant was found in heterozygous state -

Brugada syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 19, 2022

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1690 of the SCN5A protein (p.Asp1690Asn). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with Brugada syndrome (PMID: 23085483, 27108952). ClinVar contains an entry for this variant (Variation ID: 403420). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). Experimental studies have shown that this missense change affects SCN5A function (PMID: 23085483, 27108952). 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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 04, 2023

Not observed at significant frequency in large population cohorts (gnomAD); A published functional study suggests that the p.(D1690N) variant results in loss-of-function phenotype (PMID: 27108952); 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: 23085483, 30662450, 30203441, 33131149, 34546463, 32268277, 26173111, 27108952) -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 24, 2024

The p.D1690N variant (also known as c.5068G>A), located in coding exon 27 of the SCN5A gene, results from a G to A substitution at nucleotide position 5068. The aspartic acid at codon 1690 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been reported in several individuals with Brugada syndrome; however, in two cases it co-occurred with other alterations in SCN5A (Núñez L et al. Heart Rhythm, 2013 Feb;10:264-72; Selga E et al. PLoS ONE, 2015 Jul;10:e0132888; Zeng Z et al. Mol Med Rep, 2016 Jun;13:5216-22). In vitro functional studies suggest this alteration results in reduced sodium current, but such studies do not always reflect function in vivo (Núñez L et al. Heart Rhythm, 2013 Feb;10:264-72; Zeng Z et al. Mol Med Rep, 2016 Jun;13:5216-22; Pérez-Hernández M et al. JCI Insight, 2018 Sep;3: pii: 96291). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.080

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.96

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

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

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

M_CAP

Pathogenic

0.92

MetaRNN

Pathogenic

0.93

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.3

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

MutationTaster

Benign

1.0

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

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-4.8

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

REVEL

Pathogenic

0.84

Sift

Uncertain

0.022

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

Sift4G

Uncertain

0.024

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

Polyphen

1.0

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

Vest4

0.92

MutPred

0.63

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

MVP

0.95

MPC

1.4

ClinPred

0.99

GERP RS

4.4

Varity_R

0.67

gMVP

0.96

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