rs199473133
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP2PP3
The NM_000335.5(SCN5A):c.1855C>T(p.Leu619Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000502 in 1,534,778 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 Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000049 ( 0 hom. )
Consequence
SCN5A
NM_000335.5 missense
NM_000335.5 missense
Scores
5
9
6
Clinical Significance
Conservation
PhyloP100: 6.60
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 Uncertain_significance. Variant got 4 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). The gene has 99 curated pathogenic missense variants (we use a threshold of 10). The gene has 60 curated benign missense variants. GenCC has associacion of the 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, 0.83
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| SCN5A | ENST00000413689.6 | c.1855C>T | p.Leu619Phe | missense_variant | 12/28 | 5 | NM_001099404.2 | ENSP00000410257.1 | ||
| SCN5A | ENST00000423572.7 | c.1855C>T | p.Leu619Phe | missense_variant | 12/28 | 1 | NM_000335.5 | ENSP00000398266.2 |
Frequencies
GnomAD3 genomes 0.0000591 AC: 9AN: 152170Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000313 AC: 6AN: 191946Hom.: 0 AF XY: 0.0000197 AC XY: 2AN XY: 101346
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GnomAD4 exome AF: 0.0000492 AC: 68AN: 1382608Hom.: 0 Cov.: 30 AF XY: 0.0000502 AC XY: 34AN XY: 677598
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GnomAD4 genome 0.0000591 AC: 9AN: 152170Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74348
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain: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 | Dec 11, 2023 | This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 619 of the SCN5A protein (p.Leu619Phe). This variant is present in population databases (rs199473133, gnomAD 0.008%). This missense change has been observed in individuals with SCN5A-related conditions (PMID: 12673799, 30193851). ClinVar contains an entry for this variant (Variation ID: 67693). 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: 12673799). 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 | GeneDx | Oct 26, 2023 | Reported in the literature in patients with LQTS or Brugada syndrome; however, segregation data are uninformative, and some individuals harbor additional variants in other genes (PMID: 12673799, 14998624, 20129283, 30193851); Published functional studies demonstrate a damaging effect; variant expressed in HEK cells results in increased sustained sodium channel current compared to wild-type, causing prolonged depolarization and a speeding of recovery from inactivation (PMID: 12673799); however, this in vitro assay may not accurately represent biological function; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Variant occurs at a position within the cytoplasmic linker connecting domains I and II of the sodium channel that is conserved in mammals (PMID: 12673799); This variant is associated with the following publications: (PMID: 19027780, 29728395, 23414114, 22378279, 25637381, 14998624, 17504259, 12673799, 31589614, 26582918, 30193851, 30203441, 20129283) - |
Cardiac arrhythmia Uncertain:2
| 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 phenylalanine at codon 619 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). An experimental functional study has shown that this variant may impact the cardiac sodium channel function of the SCN5A protein (PMID: 12673799). This variant has been reported in two infants affected with long QT syndrome (PMID: 12673799, 14998624) as well as in two unaffected family members of one infant (PMID: 12673799). It has also been reported in individuals affected with Brugada syndrome (PMID: 20129283, 30193851). One of these individuals also carried a pathogenic variant in the same gene (PMID: 20129283). Additionally, this variant has been reported in two individuals in a healthy control population (PMID: 23414114). This variant has been identified in 9/223308 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 | Mar 20, 2023 | This missense variant replaces leucine with phenylalanine at codon 619 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). An experimental functional study has shown that this variant may impact the cardiac sodium channel function of the SCN5A protein (PMID: 12673799). This variant has been reported in two infants affected with long QT syndrome (PMID: 12673799, 14998624) as well as in two unaffected family members of one infant (PMID: 12673799). It has also been reported in individuals affected with Brugada syndrome (PMID: 20129283, 30193851). One of these individuals also carried a pathogenic variant in the same gene (PMID: 20129283). Additionally, this variant has been reported in two individuals in a healthy control population (PMID: 23414114). This variant has been identified in 9/223308 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. - |
SCN5A-related disorder Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 21, 2022 | The SCN5A c.1855C>T variant is predicted to result in the amino acid substitution p.Leu619Phe. This variant has been reported in multiple individuals with Long QT or Brugada syndrome (Wehrens et al. 2003. PubMed ID: 12673799; Lupoglazoff et al. 2004. PubMed ID: 14998624; Kapplinger et al. 2009. PubMed ID: 20129283; Table S2 - Berthome et al. 2018. PubMed ID: 30193851). Functional studies found this variant increased sustained sodium channel current resulting in a prolonged depolarization (Wehrens et al. 2003. PubMed ID: 12673799). This variant is reported in 0.0085% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-38645238-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
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 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 12, 2021 | - - |
Long QT syndrome Uncertain:1
| Uncertain significance, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
Cardiovascular phenotype Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 05, 2022 | The c.1855C>T (p.L619F) alteration is located in exon 12 (coding exon 11) of the SCN5A gene. This alteration results from a C to T substitution at nucleotide position 1855, causing the leucine (L) at amino acid position 619 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Long QT syndrome 3 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Dec 18, 2018 | The SCN5A c.1855C>T (p.Leu619Phe) variant is a missense variant that has been reported in three studies, in which it is found in a heterozygous state in two infants with long QT syndrome (LQTS) (Wehrens et al. 2003; Lupoglazoff et al. 2004). One neonate presented with fetal arrhythmia, collapse torsades de pointes, and ventricular tachycardia and also carried variants in two other genes, including KCNQ1 and HERG. In the other family, the infant's mother and maternal grandmother had borderline prolonged QTc and carried the variant. The variant was absent in the father or older sibling who normal QT intervals. The p.Leu619Phe variant was also found in a 40 year old individual with Brugada syndrome who was also heterozygous for a second truncating variant in SCN5A (Kapplinger et al. 2010). The p.Leu619Phe variant was absent from 150 control subjects but is reported at a frequency of 0.000077 in the European (non-Finnish) population of the Genome Aggregation Database. Functional studies demonstrated the p.Leu619Phe mutant Na+ channels caused increased sustained Na+ current and augmented Na+ channel window current. Based on the collective evidence, the p.Leu619Phe variant is classified as a variant of unknown significance but suspicious for long QT syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
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:12673799;PMID:14998624;PMID:20129283;PMID:22378279). 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
CardioboostCm
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
.;.;.;.;.;D;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D;D;D;D;D;D;.;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
.;M;.;.;.;M;.;.;.
PrimateAI
Benign
T
PROVEAN
Benign
N;N;N;N;N;N;N;N;N
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D;D;D;D;D;D
Sift4G
Benign
T;T;T;T;T;T;T;T;T
Polyphen
P;P;.;P;.;P;P;.;.
Vest4
MVP
MPC
0.97
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at