rs199473250

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP2

The NM_000335.5(SCN5A):ā€‹c.4339A>Cā€‹(p.Ile1447Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000378 in 1,612,560 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1447T) has been classified as Pathogenic.

Frequency

Genomes: š‘“ 0.000026 ( 0 hom., cov: 32)
Exomes š‘“: 0.000039 ( 0 hom. )

Consequence

SCN5A
NM_000335.5 missense

Scores

2
6
12

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8O:1

Conservation

PhyloP100: 1.30
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1
In a helix (size 30) in uniprot entity SCN5A_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_000335.5
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr3-38556535-A-G is described in Lovd as [Pathogenic].
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.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SCN5ANM_001099404.2 linkc.4342A>C p.Ile1448Leu missense_variant Exon 25 of 28 ENST00000413689.6 NP_001092874.1 Q14524H9KVD2
SCN5ANM_000335.5 linkc.4339A>C p.Ile1447Leu missense_variant Exon 25 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.4342A>C p.Ile1448Leu missense_variant Exon 25 of 28 5 NM_001099404.2 ENSP00000410257.1 H9KVD2
SCN5AENST00000423572.7 linkc.4339A>C p.Ile1447Leu missense_variant Exon 25 of 28 1 NM_000335.5 ENSP00000398266.2 Q14524-2

Frequencies

GnomAD3 genomes
AF:
0.0000264
AC:
4
AN:
151454
Hom.:
0
Cov.:
32
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:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000362
AC:
9
AN:
248530
Hom.:
0
AF XY:
0.0000223
AC XY:
3
AN XY:
134748
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000465
Gnomad NFE exome
AF:
0.0000621
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000390
AC:
57
AN:
1461106
Hom.:
0
Cov.:
36
AF XY:
0.0000413
AC XY:
30
AN XY:
726728
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000672
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.000150
Gnomad4 NFE exome
AF:
0.0000387
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000264
AC:
4
AN:
151454
Hom.:
0
Cov.:
32
AF XY:
0.0000271
AC XY:
2
AN XY:
73918
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:
0.0000588
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000278
Hom.:
0
Bravo
AF:
0.0000264
ExAC
AF:
0.0000248
AC:
3
EpiCase
AF:
0.000164
EpiControl
AF:
0.0000594

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:8Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:2
Dec 28, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1448 of the SCN5A protein (p.Ile1448Leu). This variant is present in population databases (rs199473250, gnomAD 0.005%). This missense change has been observed in individual(s) with SCN5A-related conditions (PMID: 20129283, 25351510, 34935411). ClinVar contains an entry for this variant (Variation ID: 67882). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Aug 17, 2023
Revvity Omics, Revvity
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Cardiac arrhythmia Uncertain:2
Jul 20, 2024
All of Us Research Program, National Institutes of Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This missense variant replaces isoleucine with leucine at codon 1448 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Brugada syndrome, hypertrophic cardiomyopathy, long QT syndrome, and dilated cardiomyopathy (PMID: 20129283, 25904541, 25351510, 27566755, 34935411). This variant has been identified in 9/248530 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. -

Mar 28, 2023
Color Diagnostics, LLC DBA Color Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This missense variant replaces isoleucine with leucine at codon 1448 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Brugada syndrome, hypertrophic cardiomyopathy, long QT syndrome, and dilated cardiomyopathy (PMID: 20129283, 25904541, 25351510, 27566755, 34935411). This variant has been identified in 9/248530 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
Nov 13, 2014
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Benign. The p.Ile1448Leu va riant in SCN5A has been reported in 1 individual with Brugada syndrome (Kappling er 2010) and was absent from large population studies. Isoleucine (Ile) at posit ion 1448 is not conserved in mammals or evolutionarily distant species and oposs um, Tasmanian devil, wallaby, and multiple birds and fish species carry a leucin e (Leu) at this position, suggesting that this change may be tolerated. Addition al computational prediction tools suggest that this variant may not impact the p rotein, though this information is not predictive enough to rule out pathogenici ty. In summary, while the clinical significance of the p.Ile1448Leu variant is u ncertain, the presence of the variant amino acid in multiple other species, incl uding mammals, suggests that it is more likely to be benign. -

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
Apr 06, 2022
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Cardiovascular phenotype Uncertain:1
Mar 09, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.4342A>C (p.I1448L) alteration is located in exon 25 (coding exon 24) of the SCN5A gene. This alteration results from a A to C substitution at nucleotide position 4342, causing the isoleucine (I) at amino acid position 1448 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Long QT syndrome 3 Uncertain:1
Jul 04, 2022
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ACMG classification criteria: PS4 supporting, PM2 moderated -

Brugada 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 Brugada syndrome in the following publications (PMID:20129283). 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
0.051
CardioboostCm
Benign
0.062
BayesDel_addAF
Pathogenic
0.18
D
BayesDel_noAF
Pathogenic
0.18
CADD
Benign
16
DANN
Benign
0.55
DEOGEN2
Uncertain
0.61
.;.;.;.;.;D;.;.;.
Eigen
Benign
-0.73
Eigen_PC
Benign
-0.52
FATHMM_MKL
Benign
0.72
D
LIST_S2
Benign
0.66
.;T;T;T;T;T;T;.;T
M_CAP
Uncertain
0.22
D
MetaRNN
Uncertain
0.57
D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.18
D
MutationAssessor
Benign
-0.65
.;.;.;.;.;N;.;.;.
PrimateAI
Uncertain
0.53
T
PROVEAN
Benign
0.65
N;N;N;N;N;N;N;N;N
REVEL
Uncertain
0.53
Sift
Benign
1.0
T;T;T;T;T;T;T;T;T
Sift4G
Benign
1.0
T;T;T;T;T;T;T;T;T
Polyphen
0.0010
B;B;.;B;.;B;B;.;.
Vest4
0.75
MutPred
0.87
.;.;Loss of sheet (P = 0.0181);.;.;Loss of sheet (P = 0.0181);.;.;.;
MVP
0.95
MPC
0.51
ClinPred
0.050
T
GERP RS
1.8
Varity_R
0.16
gMVP
0.94

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.

Other links and lift over

dbSNP: rs199473250; hg19: chr3-38598027; API