rs150264233

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 6P and 3B. PM1PM2PP2PP3BP4_ModerateBP6

The NM_000335.5(SCN5A):c.5708C>T(p.Ser1903Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000737 in 1,614,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000041 ( 0 hom. )

Consequence

SCN5A
NM_000335.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:7O:1

Conservation

PhyloP100: 8.13

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 Uncertain_significance. Variant got 3 ACMG points.

PM1

In a domain IQ (size 29) in uniprot entity SCN5A_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_000335.5

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

Multiple lines of computational evidence support a deleterious effect 11: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, M_CAP, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.16239089).

BP6

Variant 3-38550661-G-A is Benign according to our data. Variant chr3-38550661-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48310.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=2, not_provided=1, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2 linkuse as main transcript	c.5711C>T	p.Ser1904Leu	missense_variant	28/28	ENST00000413689.6	NP_001092874.1	Q14524H9KVD2
SCN5A	NM_000335.5 linkuse as main transcript	c.5708C>T	p.Ser1903Leu	missense_variant	28/28	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.5711C>T	p.Ser1904Leu	missense_variant	28/28	5	NM_001099404.2	ENSP00000410257.1		H9KVD2
SCN5A	ENST00000423572.7 linkuse as main transcript	c.5708C>T	p.Ser1903Leu	missense_variant	28/28	1	NM_000335.5	ENSP00000398266.2		Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.000387

AC:

AN:

152260

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00135

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.000478

GnomAD3 exomes

AF:

0.000132

AC:

AN:

249274

Hom.:

AF XY:

0.0000961

AC XY:

AN XY:

135226

show subpopulations

Gnomad AFR exome

AF:

0.00181

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000410

AC:

AN:

1461676

Hom.:

Cov.:

AF XY:

0.0000344

AC XY:

AN XY:

727114

show subpopulations

Gnomad4 AFR exome

AF:

0.00149

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.000387

AC:

AN:

152378

Hom.:

Cov.:

AF XY:

0.000268

AC XY:

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.00135

Gnomad4 AMR

AF:

0.0000653

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:

0.000473

Alfa

AF:

0.0000929

Hom.:

Bravo

AF:

0.000453

ESP6500AA

AF:

0.00236

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000190

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2Benign:7Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1Other: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:18708744;PMID:20129283;PMID:22378279;PMID:22426227). -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 13, 2023	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 with diseases that have different mechanisms of pathogenicity, its clinical significance is uncertain; 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: 22378279, 20129283, 25904541, 28988457, 30847666, 25637381, 22426227, 26159999, 26332594, 24892747, 27435932, 29728395, 26746457, 34021086, 30153324, 21167176, 18708744, 30203441, Tomaselli2023[Functional], 35662881, 24055113) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 23, 2019	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 23, 2022	Variant summary: SCN5A c.5711C>T (p.Ser1904Leu) results in a non-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 0.00017 in 283812 control chromosomes (gnomAD, Bankston_2007, Kapplinger_2010, Kapplinger_2015), predominantly at a frequency of 0.0017 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 68 fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.5711C>T has been reported in at least one individual with LQTS and segregated with symptoms of disease in two family members, however only a subset of LQTS-associated genes were sequenced in these individuals (Bankston_2007). In addition, the variant has been reported in at least one individual affected with SIDS (Methner_2017). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. Several publications report experimental evidence evaluating an impact on protein function. These studies report that the variant disrupts sodium channel gate inactivation and promotes late Na+ channel currents by increasing the propensity of the channel to reopen during prolonged depolarization (Bankston_2007, Glaaser_2012). Another study reports that the variant may have a more severe electrophysiological impact in certain tissue types, as the effect in Purkinje fiber cells was more significant than that observed in a ventricular myocyte model (Iyer_2014). A recent study showed that the variant had had reduced affinity for Calmodulin binding compared to wildtype (Kang_2021). These in-vitro studies do not allow convincing conclusions about the variant effect, however, as the variant does not appear to alter the overall function of the sodium channels and it is unclear how these findings would translate in-vivo. Eight ClinVar submitters have assessed the variant since 2014: two classified the variant as of uncertain significance, four as likely benign, one as benign and one as pathogenic. Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 05, 2020	The p.Ser1904Leu variant in SCN5A has been reported in several individuals with a range of cardiac manifestations (Bankston 2007 PMID: 18708744, Kapplinger 2010 PMID: 20129283, Methner 2016 PMID: 27435932, LMM data). However, this variant has also been identified in 0.17% (42/24204) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is inconsistent with the reported prevalence of SCN5A-associated disease. This variant has also been reported in ClinVar (Variation ID: 48310). Computational prediction tools and conservation analyses predict an impact to the protein and in vitro studies suggest that the p.Ser1904Leu variant may impact protein function (Bankston 2007 PMID: 18708744, Glaaser 2012 PMID: 22426227, Kapplinger 2010 PMID: 20129283). However, this in vitro assay may not accurately represent biological function. In summary, because of the frequency, this variant is classified as likely benign. ACMG/AMP Criteria applied: PP3, PS4_Supporting, BS1. -

Death in infancy

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Forensic Genetics Laboratory, Harris County Institute of Forensic Sciences

Mar 27, 2015

- -

Brugada syndrome 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Long QT syndrome

Benign:1

Likely benign, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 18, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Cardiac arrhythmia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Nov 24, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

CardioboostCm

Uncertain

0.82

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.86

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

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.98

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

M_CAP

Pathogenic

0.83

MetaRNN

Benign

0.16

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.4

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

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-5.5

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

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

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

Sift4G

Uncertain

0.010

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

Polyphen

1.0

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

Vest4

0.53

MVP

0.96

MPC

1.3

ClinPred

0.74

GERP RS

4.9

Varity_R

0.90

gMVP

0.95

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