3-38603902-A-T

Position:

chr3-38603902-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The ENST00000423572.7(SCN5A):c.1700T>A(p.Leu567Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000372 in 1,613,842 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L567R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000040 ( 1 hom. )

Consequence

SCN5A
ENST00000423572.7 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.94

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 Uncertain_significance. Variant got 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2 linkuse as main transcript	c.1700T>A	p.Leu567Gln	missense_variant	12/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5 linkuse as main transcript	c.1700T>A	p.Leu567Gln	missense_variant	12/28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6 linkuse as main transcript	c.1700T>A	p.Leu567Gln	missense_variant	12/28	5	NM_001099404.2	ENSP00000410257	P4
SCN5A	ENST00000423572.7 linkuse as main transcript	c.1700T>A	p.Leu567Gln	missense_variant	12/28	1	NM_000335.5	ENSP00000398266	A1	Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000803

AC:

AN:

249034

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135108

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000331

GnomAD4 exome

AF:

0.0000404

AC:

AN:

1461640

Hom.:

Cov.:

AF XY:

0.0000344

AC XY:

AN XY:

727110

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

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

Alfa

AF:

0.0000450

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000826

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain: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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 21, 2024	This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 567 of the SCN5A protein (p.Leu567Gln). This variant is present in population databases (rs199473124, gnomAD no frequency). This missense change has been observed in individual(s) with Brugada syndrome (PMID: 10711933, 11076825, 29915097). ClinVar contains an entry for this variant (Variation ID: 67678). 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 have shown that this missense change affects SCN5A function (PMID: 11123251, 24573164). 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	Revvity Omics, Revvity	Dec 01, 2021	- -

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 leucine with glutamine at codon 567 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). An in-vitro functional study has shown that this variant may cause a reduction in peak current density (PMID: 24573164). Another functional study has shown that this variant may play a role in modulating inactivation of the cardiac sodium channel (PMID: 11123251). This variant has been reported in a family affected with Brugada syndrome and multiple incidences of sudden infant death (PMID: 10711933, 11901046), and in an asymptomatic individual with a family history of Brugada syndrome (PMID: 24963427). This variant has also been reported in an individual affected with sudden unexplained death (PMID: 29915097) and in multiple individuals affected with ischemic stroke (PMID: 36973604). This variant has been identified in 2/249034 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 16, 2024	This missense variant replaces leucine with glutamine at codon 567 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). An in-vitro functional study has shown that this variant may cause a reduction in peak current density (PMID: 24573164). Another functional study has shown that this variant may play a role in modulating inactivation of the cardiac sodium channel (PMID: 11123251). This variant has been reported in a family affected with Brugada syndrome and multiple incidences of sudden infant death (PMID: 10711933, 11901046), and in an asymptomatic individual with a family history of Brugada syndrome (PMID: 24963427). This variant has also been reported in an individual affected with sudden unexplained death (PMID: 29915097) and in multiple individuals affected with ischemic stroke (PMID: 36973604). This variant has been identified in 2/249034 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

Pathogenic:1

Likely pathogenic, flagged submission

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 15, 2021

Variant summary: SCN5A c.1700T>A (p.Leu567Gln) results in a non-conservative amino acid change located in the Voltage-gated Na+ ion channel, cytoplasmic domain (IPR024583) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 249034 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1700T>A has been reported in the literature in one individual with ST-segment elevation in leads V1-V3 and a suspected diagnosis of Brugada syndrome (Priori_2000). The pedigree as reported for this individual was non-informative due to insufficient genotyped affected family members as all were deceased (due to sudden death). Additionally, at-least three unaffected relatives with this variant were reported. At-least one additional case report of an asymptomatic pregnancy with this variant and a family history of sudden cardiac deaths has been reported (Giambanco_2014). The variant has also been reported with conflicting interpretations of pathogenicity (P and VUS respectively) in two cases within the setting of sudden unexplained death in the young (SUDY) (Shanks_2018, Pearman_2020). Lastly, one recent report has classified this variant as a VUS citing caution when extrapolating functional testing to the likelihood of variant pathogenicity (Rochtus_2020). Since the ascertained penetrance of Brugada Syndrome due to this variant appears to be lower than expected, no conclusions can be drawn from these data. At least two publications report experimental evidence evaluating an impact on protein channel function, however, does not allow convincing conclusions about the variant effect (Wan_2001 and Hoshi_2014). Subsequent reports evaluating all published literature have concluded that the relationship between in vitro assessment of channel function and Brugada syndrome clinical phenotype is weak and there exists no relationship between any aspect of channel function and conduction abnormalities/sudden cardiac death or spontaneous Brugada ECG pattern (Pearman_2020). Four 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 uncertain significance. -

Brugada syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Mar 26, 2024

- -

Atrial fibrillation, familial, 10

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 04, 2020

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Autism

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Centre for Addiction & Mental Health, Centre for Addiction & Mental Health

Gene not previously associated with disease; independent supportng evidence needed -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2020

The c.1700T>A (p.L567Q) alteration is located in exon 12 (coding exon 11) of the SCN5A gene. This alteration results from a T to A substitution at nucleotide position 1700, causing the leucine (L) at amino acid position 567 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Brugada 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 Brugada syndrome in the following publications (PMID:10711933;PMID:11901046;PMID:11076825;PMID:11123251). 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

0.070

CardioboostCm

Benign

0.0015

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.060

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.41

.;.;.;.;.;T;.;.;.

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.16

FATHMM_MKL

Benign

0.27

LIST_S2

Uncertain

0.88

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

M_CAP

Pathogenic

0.54

MetaRNN

Uncertain

0.72

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

MetaSVM

Uncertain

0.040

MutationAssessor

Benign

1.6

.;L;.;.;.;L;.;.;.

MutationTaster

Benign

0.63

N;N;N;N;N;N;N;N;N;N

PrimateAI

Benign

0.37

PROVEAN

Benign

0.89

N;N;N;N;N;N;N;N;N

REVEL

Uncertain

0.60

Sift

Benign

0.31

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

Sift4G

Benign

0.29

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

Polyphen

0.41

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

Vest4

0.82

MutPred

0.74

Gain of phosphorylation at T570 (P = 0.1012);Gain of phosphorylation at T570 (P = 0.1012);Gain of phosphorylation at T570 (P = 0.1012);Gain of phosphorylation at T570 (P = 0.1012);Gain of phosphorylation at T570 (P = 0.1012);Gain of phosphorylation at T570 (P = 0.1012);Gain of phosphorylation at T570 (P = 0.1012);Gain of phosphorylation at T570 (P = 0.1012);Gain of phosphorylation at T570 (P = 0.1012);

MVP

0.91

MPC

0.96

ClinPred

0.27

GERP RS

3.0

Varity_R

0.086

gMVP

0.74

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