3-38555720-T-C

Position:

chr3-38555720-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP2PP3_ModeratePP5

The ENST00000423572.7(SCN5A):c.4475A>G(p.Lys1492Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000626 in 1,613,916 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 0.000033 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000066 ( 0 hom. )

Consequence

SCN5A
ENST00000423572.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:10O:1

Conservation

PhyloP100: 7.97

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 8 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in ENST00000423572.7

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

MetaRNN computational evidence supports a deleterious effect, 0.9

PP5

Variant 3-38555720-T-C is Pathogenic according to our data. Variant chr3-38555720-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67898.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Pathogenic=1, Uncertain_significance=10, not_provided=1}. Variant chr3-38555720-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2 linkuse as main transcript	c.4478A>G	p.Lys1493Arg	missense_variant	26/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5 linkuse as main transcript	c.4475A>G	p.Lys1492Arg	missense_variant	26/28	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.4478A>G	p.Lys1493Arg	missense_variant	26/28	5	NM_001099404.2	ENSP00000410257	P4
SCN5A	ENST00000423572.7 linkuse as main transcript	c.4475A>G	p.Lys1492Arg	missense_variant	26/28	1	NM_000335.5	ENSP00000398266	A1	Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251474

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135910

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:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000657

AC:

AN:

1461816

Hom.:

Cov.:

AF XY:

0.0000674

AC XY:

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.0000782

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152100

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74292

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000129

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:10Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	SCN5A: PS4:Moderate, PP3, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 14, 2024	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 1493 of the SCN5A protein (p.Lys1493Arg). This variant is present in population databases (rs199473260, gnomAD 0.002%). This missense change has been observed in individuals with autosomal dominant long QT syndrome, atrial fibrillation, and/or supraventricular ectopy (PMID: 19167345, 19716085, 23861362; Invitae). ClinVar contains an entry for this variant (Variation ID: 67898). 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: 19167345). For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 18, 2019	- -

Long QT syndrome 3

Pathogenic:1Uncertain:2

Uncertain significance, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Oct 29, 2024	This variant in SCN5A, p.(Lys1492Arg), is rare in gnomAD (v2.1, 0.000039 maf in NFE) and has been reported in individuals with atrial fibrillation (PMID: 19167345), and long QT syndrome (PMID: 19716085, PMID: 32893267). The REVEL score for this variant is 0.911 which supports pathogenicity. Functional studies show some impact on protein function with limited controls. Based on this information we classify this variant as a variant of uncertain significance. PS4_Supporting, PP3_Moderate. -
Likely pathogenic, flagged submission	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant p.K1492R in SCN5A (NM_000335.5) has been previously reported in individuals with atrial fibrillation, long QT syndrome and supraventricular ectopy. It has been reported as a secondary variant in an exome study performed for cardiac diseases (Li Q et al,.Kapplinger JD et al, Ng D et al)The p.K1492R variant is observed in 4/1,13,768 (0.0035%) alleles from individuals of European (NonFinnish) background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. It has been submitted to ClinVar with conflicting interpretations of Uncertain Significance/Likely Pathogenic. Experimental studies have shown that this missense change leads to a positive shift in voltage-dependence of sodium channel inactivation and enhanced cardiomyocyte excitability consistent with a gain-of-function effect ( Li Q et al). The p.K1492R missense variant is predicted to be damaging by both SIFT and PolyPhen2. The lysine residue at codon 1492 of SCN5A is conserved in all mammalian species. The nucleotide c.4475 in SCN5A is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance -

Cardiac arrhythmia

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 06, 2024	This missense variant replaces lysine with arginine at codon 1493 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).Functional studies have shown that this variant impacts voltage-dependence of sodium channel inactivation and cardiomyocyte excitability consistent with a gain-of-function effect (PMID: 19167345, 33712541). This variant has been reported in two related individuals affected with atrial fibrillation (PMID: 19167345), in two individuals affected with and another two individuals suspected to be affected with long QT syndrome (PMID: 19716085, 32893267). This variant has also been found in one individual affected with dilated cardiomyopathy, one individual with hypertrophic cardiomyopathy (PMID: 38489124), and another with a history of supraventricular ectopy (PMID: 23861362). This variant has been identified in 5/282810 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	Color Diagnostics, LLC DBA Color Health	May 15, 2023	This missense variant replaces lysine with arginine at codon 1493 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).Functional studies have shown that this variant impacts voltage-dependence of sodium channel inactivation and cardiomyocyte excitability consistent with a gain-of-function effect (PMID: 19167345, 33712541). This variant has been reported in two related individuals affected with atrial fibrillation (PMID: 19167345), in one individual affected with and another two individuals suspected to be affected with long QT syndrome (PMID: 19716085, 32893267), in one individual with a history of supraventricular ectopy (PMID: 23861362), and in two related individuals affected with atrial fibrillation (PMID: 19167345). This variant has been identified in 5/282810 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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jul 21, 2023

Variant summary: SCN5A c.4478A>G (p.Lys1493Arg) results in a conservative amino acid change located in the Voltage-gated sodium channel alpha subunit, inactivation gate (IPR044564) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251474 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4478A>G has been reported in the literature in settings of multi-gene panel testing or whole exome sequencing in individuals affected with Long QT Syndrome (e.g. Mullally_2013, Kapplinger_2009, Lieve_2013), with some patients carrying unknown variants in causative genes (e.g. Mullally_2013), in patients affected with lone atrial fibrilation (e.g. Li_2009), or with coronary artery disease risk (e.g. Ng_2013), without definitive evidence of causation. These report(s) do not provide unequivocal conclusions about association of the variant with Long QT Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function in vitro, suggesting altered cellular hyperexcitability in the cardiac sodium channel (e.g. Li_2009). The following publications have been ascertained in the context of this evaluation (PMID: 19716085, 19167345, 23631430, 23174487, 23861362). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters 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

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Oct 19, 2020

Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as 3A-VUS. Following criteria are met: 0103 - Loss of function and gain of function are both known mechanisms of disease in this gene. Loss of function is usually associated with Brugada syndrome, whereas gain of function is usually associated with LQTS, however some variants simultaneously result in both a loss and gain of function, and have been observed in patients with LQTS, Brugada syndrome, and patients with a blended phenotype. Additionally, different studies have shown conflicting mechanisms in association with atrial fibrillation (PMID: 29806494, PMID: 19167345). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from lysine to arginine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (5 heterozygotes, 0 homozygotes). (SP) 0309 - A single amino acid inframe deletion at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions, but very high conservation. (I) 0600 - Variant is located at an acetylated residue in the annotated DIII-DIV intracellular linker region which mediates sodium channel inactivation (NCBI, PDB, Phosphosite, PMID: 23840796). (I) 0704 - Another variant comparable to the one identified in this case has limited previous evidence for pathogenicity. An inframe deletion of the same residue has previously been reported to segregate in a large family with cardiac conduction disease. The affected individuals did not exhibit signs of either Brugada syndrome or LQTS however, functional studies of the variant demonstrated both a gain and loss of function (PMID: 23840796). (SP) 0808 - Previous reports of pathogenicity for this variant are conflicting. The variant has previously been reported in patients with LQTS and lone atrial fibrillation, and was not present in an unaffected family member however, it has also been classified as both likely pathogenic and a VUS in relation to atrial fibrillation and Brugada syndrome, respectively (ClinVar, HGMD, LOVD, PMID: 19167345, PMID: 25904541). It has also previously been observed at VCGS in a patient with probable LQTS and classified as a 3A-VUS. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies demonstrated a significant positive shift in voltage-dependence of inactivation and a large ramp current near resting membrane potential, indicating a gain of function (PMID: 19167345). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

SCN5A-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 03, 2022

The SCN5A c.4478A>G variant is predicted to result in the amino acid substitution p.Lys1493Arg. This variant has been reported in two patients with atrial fibrillation from a single family (Li et al. 2009. PubMed ID: 19167345) and in two patients with long QT syndrome (Table S3, Kapplinger et al. 2009. PubMed ID: 19716085). Functional experiments demonstrated this variant led to a gain of function effect (Li et al. 2009. PubMed ID: 19167345). This variant is reported in 0.0039% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-38597211-T-C). This variant is reported in ClinVar with conflicting interpretations of uncertain and likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/67898/). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 22, 2022

The c.4478A>G (p.K1493R) alteration is located in exon 26 (coding exon 25) of the SCN5A gene. This alteration results from a A to G substitution at nucleotide position 4478, causing the lysine (K) at amino acid position 1493 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Congenital long QT 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 Long QT syndrome in the following publications (PMID:19167345;PMID:19716085). 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

0.30

CardioboostCm

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

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

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.97

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

M_CAP

Pathogenic

0.51

MetaRNN

Pathogenic

0.90

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.1

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

MutationTaster

Benign

0.99

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

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-2.8

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

REVEL

Pathogenic

0.91

Sift

Uncertain

0.013

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

Sift4G

Uncertain

0.040

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

Polyphen

0.52

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

Vest4

0.95

MVP

0.99

MPC

1.0

ClinPred

0.96

GERP RS

4.5

Varity_R

0.74

gMVP

0.81

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