rs199473266

Variant names:

• chr3-38555697-G-C
• rs199473266
• NM_001099404.2:c.4501C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3 PP5

The NM_000335.5(SCN5A):​c.4498C>G​(p.Leu1500Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000246 in 1,461,748 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: not found (cov: 30)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: SCN5A NM_000335.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:4 O:1
• Conservation: PhyloP100: 3.36

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 7 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 62) in uniprot entity SCN5A_HUMAN there are 15 pathogenic changes around while only 1 benign (94%) in NM_000335.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the SCN5A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 99 curated pathogenic missense variants (we use a threshold of 10). The gene has 60 curated benign missense variants. Gene score misZ: 2.7504 (below the threshold of 3.09). Trascript score misZ: 4.8279 (above the threshold of 3.09). GenCC associations: The gene is linked to 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: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 3-38555697-G-C is Pathogenic according to our data. Variant chr3-38555697-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67904.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=5, Uncertain_significance=4, Pathogenic=1, not_provided=1}. Variant chr3-38555697-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.4501C>G	p.Leu1501Val	missense_variant	Exon 26 of 28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.4498C>G	p.Leu1500Val	missense_variant	Exon 26 of 28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.4501C>G	p.Leu1501Val	missense_variant	Exon 26 of 28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.4498C>G	p.Leu1500Val	missense_variant	Exon 26 of 28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251446 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135894

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: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000246 AC: 36 AN: 1461748 Hom.: 0 Cov.: 31 AF XY: 0.0000330 AC XY: 24 AN XY: 727196

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: 0.0000297

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 30

Alfa AF: 0.0000312 Hom.: 0

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:4 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:2

Sep 22, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Leu1501Val variant (rs199473266) has been reported in several individuals with long QT syndrome, a single individual with Brugada syndrome, and was absent from controls (Kapa 2014, Kapplinger 2009, Kapplinger 2010, Savastano 2014, and Splawski 2000). The p.Leu1501Val variant is listed in the Genome Aggregation Database (gnomAD) browser with an allele frequency of 0.0045% in the Non-Finnish European population (identified in 5 out of 111,706 chromosomes), and is classified as likely pathogenic in ClinVar (Variant ID: 67904). Functional evidence demonstrates that the p.Leu1501Val variant reduces SCN5A sodium channel peak current density when co-expressed with wild type SCN5A; however, the clinical relevance of this observation is unclear. The leucine at codon 1501 is highly conserved considering 9 species up to zebrafish (Alamut software v2.10.0), and computational analyses suggest that this variant affects the structure/function of the SCN5A protein (SIFT: damaging, PolyPhen2: probably damaging, MutationTaster: disease causing). While the p.Leu1501Val variant is a strong candidate for a likely pathogenic classification, the clinical significance cannot be determined with certainty because the functional data does not have a well-established connection to disease. -

Jul 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1501 of the SCN5A protein (p.Leu1501Val). This variant is present in population databases (rs199473266, gnomAD 0.004%). This missense change has been observed in individuals with long QT syndrome (PMID: 10973849, 19841300, 24721456, 30193851). ClinVar contains an entry for this variant (Variation ID: 67904). 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 disruptive. Experimental studies have shown that this missense change affects SCN5A function (PMID: 24573164). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -

Apr 02, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in association with Brugada syndrome, fever-induced Brugada syndrome, long QT syndrome (LQTS), and sudden cardiac death (SCD) in published literature (PMID: 19716085, 20129283, 10973849, 19841300, 24721456, 30193851, 20102864, 23631430, 36516610); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis supports a deleterious effect on splicing; Did not segregate interdependently with Brugada syndrome in two families (PMID: 28494446, 29956481); Functional analysis has been unclear on this variant's impact on protein function (PMID: 24573164, 30369311, 29606593); This variant is associated with the following publications: (PMID: 24136861, 19716085, 10973849, 19841300, 24721456, 29956481, 31447099, 30059973, 28494446, 30193851, 33221895, 33131149, 34135346, 30203441, 34546463, 20129283, 20102864, 23631430, 36516610, 37942788, 32533187, 30369311, 29606593, 24573164, 22840528, 21185501) -

Brugada syndrome 1 Pathogenic:1

Mar 31, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. 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 1 (MIM#601144) and sick sinus syndrome 1 (SSS) (MIM#608567), whereas gain of function is usually associated with long QT syndrome-3 (LQTS) (MIM#603830). Dilated cardiomyopathy 1E (DCM) (MIM#601154) can be caused by variants with either a loss or gain of function mechanism (PMID: 29798782). Dominant-negative has also been demonstrated as a possible mechanism associated with Brugada syndrome (PMIDs: 22739120, 24573164). (I) 0108 - This gene is associated with both recessive and dominant disease. Most conditions associated with this gene are dominantly inherited; however SSS is caused by biallelic variants (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from leucine to valine. (I) 0304 - Variant is present in gnomAD <0.01 (v2: 5 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a minor amino acid change. (SP) 0600 - Variant is located in the annotated DIII/DIV interdomain linker (PMID: 27566755). (I) 0710 - Another variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. The p.(Leu1500Pro) has been classified once as a VUS (ClinVar). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in at least five individuals with either LQTS or Brugada syndrome (ClinVar, PMIDs: 10973849, 20129283, 27566755). (SP) 1010 - Functional evidence for this variant is inconclusive. While the mutant construct transfected into HEK293T cells did not demonstrate abnormal protein function, co-transfection of mutant and WT constructs resulted in a reduction of peak current density (PMID: 24573164). (I) 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 Pathogenic:1

Aug 31, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SCN5A c.4501C>G variant is predicted to result in the amino acid substitution p.Leu1501Val. This variant has frequently been reported in the literature individuals with various cardiovascular phenotypes (Long QT/Brugada syndromes) (Splawski et al 2000. PubMed ID: 10973849; Table S2, Berthome et al. 2019. PubMed ID: 30193851; Lacaze et al. 2021. PubMed ID: 34135346). This variant is reported in 0.0044% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-38597188-G-C). Taken together, this variant is interpreted as likely pathogenic. -

SUDDEN INFANT DEATH SYNDROME;C1832680:Dilated cardiomyopathy 1E;C1837845:Sick sinus syndrome 1;C1859062:Long QT syndrome 3;C1879286:Progressive familial heart block, type 1A;C2751898:Ventricular fibrillation, paroxysmal familial, type 1;C3151464:Atrial fibrillation, familial, 10;C4551804:Brugada syndrome 1 Pathogenic:1

Mar 25, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Long QT syndrome Pathogenic:1

Jun 24, 2020

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SCN5A c.4501C>G (p.Leu1501Val) results in a conservative amino acid change located in the Ion transport domain of 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 2e-05 in 255846 control chromosomes. c.4501C>G has been reported in the literature in multiple individuals affected with Long QT Syndrome (e.g. Splawski_2000, Kapplinger_2009, Kapa_2009), Brugada Synrome (Kapplinger_2010, Crotti_2012), or SCD (Adabag_2010, Goldenberg_2011). These data indicate that the variant is very likely to be associated with disease. Experimental studies have shown that this variant leads to a reduction of peak current densities when co-expressed with wild-type SCN5A (Hoshi_2014). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely pathogenic n=2, VUS n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Long QT syndrome 3 Pathogenic:1

Oct 23, 2017

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4501C>G (p.Leu1501Val) variant in the SCN5A has been observed in multiple individuals with Long QT syndrome (PMID: 10973849, 19841300) and one individual with Brugada syndrome (PMID: 24721456). In addition, experimental studies have shown that this missense change leads to altered SCN5A protein function (PMID: 24573164). Therefore, this variant in the SCN5A gene is classified as likely pathogenic. -

Cardiovascular phenotype Uncertain:1

Dec 07, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4501C>G (p.L1501V) alteration is located in exon 26 (coding exon 25) of the SCN5A gene. This alteration results from a C to G substitution at nucleotide position 4501, causing the leucine (L) at amino acid position 1501 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Cardiac arrhythmia Uncertain:1

Aug 07, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces leucine with valine at codon 1501 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). A functional study has shown that this variant may cause a reduction in sodium current density (PMID: 24573164). An RNA study has shown that this variant partially disrupts RNA splicing but due to the activation of a cryptic donor site but the mutant allele also produced the normal transcript (PMID: 30369311). This variant has been reported in four individuals with Brugada syndrome (PMID: 24721456, 30193851, 32533187, 33221895), two individuals with long QT syndrome (PMID: 10973849, 19841300), one individual with sudden cardiac death in his 70s (PMID: 34135346), as well as two asymptomatic individuals aged 70 years and older without a history of cardiovascular events (PMID: 34135346). This variant has been detected in a small family affected with Brugada syndrome, in which a variant in a different gene, but not this SCN5A variant, appeared to segregate with disease (PMID: 28494446). This variant has been identified in 5/251446 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Due to the conflicting clinical observations, the role of this variant in disease cannot be determined conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Congenital long QT syndrome Other:1

-

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:10973849;PMID:19716085;PMID:19841300). 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	Pathogenic	0.89
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.77	.;.;.;.;.;D;.;.;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.6	.;.;.;.;.;H;.;.;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-2.8	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;B;.;D;.;D;D;.;.
Vest4		0.72
MutPred		0.79		.;.;Gain of methylation at K1500 (P = 0.0423);.;.;Gain of methylation at K1500 (P = 0.0423);.;.;.;
MVP		0.98
MPC		1.4
ClinPred		0.87	D
GERP RS		2.5
Varity_R		0.83
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.54		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.54		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs199473266; hg19: chr3-38597188;