rs199473266

Variant summary

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

The NM_000335.5(SCN5A):ā€‹c.4498C>Gā€‹(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 š‘“: 0.000025 ( 0 hom. )

Consequence

SCN5A
NM_000335.5 missense

Scores

11
8
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:4O:1

Conservation

PhyloP100: 3.36
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 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
MetaRNN computational evidence supports a deleterious effect, 0.938
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: {Uncertain_significance=4, Pathogenic=1, Likely_pathogenic=5, 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
SCN5ANM_001099404.2 linkc.4501C>G p.Leu1501Val missense_variant Exon 26 of 28 ENST00000413689.6 NP_001092874.1 Q14524H9KVD2
SCN5ANM_000335.5 linkc.4498C>G p.Leu1500Val missense_variant Exon 26 of 28 ENST00000423572.7 NP_000326.2 Q14524-2Q86V90

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SCN5AENST00000413689.6 linkc.4501C>G p.Leu1501Val missense_variant Exon 26 of 28 5 NM_001099404.2 ENSP00000410257.1 H9KVD2
SCN5AENST00000423572.7 linkc.4498C>G p.Leu1500Val missense_variant Exon 26 of 28 1 NM_000335.5 ENSP00000398266.2 Q14524-2

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
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:
0.0000440
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
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:
0.0000297
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:6Uncertain:4Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:1Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesSep 22, 2017The 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. -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 11, 2024This 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. -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxApr 02, 2024Reported 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
Likely pathogenic, criteria provided, single submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteMar 31, 2022Based 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
Likely pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesAug 31, 2022The 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
Likely pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMar 25, 2024- -
Long QT syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJun 24, 2020Variant 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
Likely pathogenic, criteria provided, single submitterclinical testingHuman Genome Sequencing Center Clinical Lab, Baylor College of MedicineOct 23, 2017The 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
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 07, 2022The 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
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthAug 07, 2023This 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
not provided, no classification providedliterature onlyCardiovascular 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: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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs199473266; hg19: chr3-38597188; API