rs199473260

chr3-38555720-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3_Moderate PP5

The NM_001099404.2(SCN5A):c.4478A>G(p.Lys1493Arg) 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 NM_001099404.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:8 O:1
• Conservation: PhyloP100: 7.97

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]

ACMG classification

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 NM_001099404.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SCN5A
• 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: {Pathogenic=1, not_provided=1, Uncertain_significance=8, Likely_pathogenic=2}. Variant chr3-38555720-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.4478A>G	p.Lys1493Arg	missense_variant	26/28	ENST00000413689.6
SCN5A	NM_000335.5	c.4475A>G	p.Lys1492Arg	missense_variant	26/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.4478A>G	p.Lys1493Arg	missense_variant	26/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.4475A>G	p.Lys1492Arg	missense_variant	26/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152100 Hom.: 0 Cov.: 31

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: 4 AN: 251474 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135910

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: 96 AN: 1461816 Hom.: 0 Cov.: 31 AF XY: 0.0000674 AC XY: 49 AN XY: 727218

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: 5 AN: 152100 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74292

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.: 0

Bravo AF: 0.0000491

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:8 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain: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	Invitae	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:1 Uncertain:1

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 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genomics England Pilot Project, Genomics England	-	- -

Cardiac arrhythmia Uncertain:2

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. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 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. -

Atrial fibrillation Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Jun 24, 2013

- -

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. -

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
CardioboostArm	Pathogenic	1.0
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.51
Cadd	Pathogenic	26
Dann	Uncertain	1.0
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	0.99	D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.88	D
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	D
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

Other links and lift over

dbSNP: rs199473260; hg19: chr3-38597211;