chr3-38550671-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP2PP3_Strong

The NM_001099404.2(SCN5A):ā€‹c.5701G>Cā€‹(p.Glu1901Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,886 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 (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 33)
Exomes š‘“: 0.0000068 ( 0 hom. )

Consequence

SCN5A
NM_001099404.2 missense

Scores

13
5
2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4O:1

Conservation

PhyloP100: 7.91
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 9 ACMG points.

PM1
In a region_of_interest Interaction with FGF13 (size 62) in uniprot entity SCN5A_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_001099404.2
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 4.7729 (greater than threshold 3.09). GenCC has associacion of 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, 0.96

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SCN5ANM_001099404.2 linkuse as main transcriptc.5701G>C p.Glu1901Gln missense_variant 28/28 ENST00000413689.6 NP_001092874.1
SCN5ANM_000335.5 linkuse as main transcriptc.5698G>C p.Glu1900Gln missense_variant 28/28 ENST00000423572.7 NP_000326.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SCN5AENST00000413689.6 linkuse as main transcriptc.5701G>C p.Glu1901Gln missense_variant 28/285 NM_001099404.2 ENSP00000410257 P4
SCN5AENST00000423572.7 linkuse as main transcriptc.5698G>C p.Glu1900Gln missense_variant 28/281 NM_000335.5 ENSP00000398266 A1Q14524-2

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152202
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000321
AC:
8
AN:
249290
Hom.:
0
AF XY:
0.00000739
AC XY:
1
AN XY:
135232
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000232
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000684
AC:
10
AN:
1461684
Hom.:
0
Cov.:
31
AF XY:
0.00000413
AC XY:
3
AN XY:
727116
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000224
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152202
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74352
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.0000248
AC:
3

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

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 submitterclinical testingFulgent Genetics, Fulgent GeneticsAug 26, 2021- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 29, 2024This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 1901 of the SCN5A protein (p.Glu1901Gln). This variant is present in population databases (rs199473325, gnomAD 0.03%). This missense change has been observed in individual(s) with long QT syndrome (PMID: 19716085). ClinVar contains an entry for this variant (Variation ID: 68007). 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: 28087622). 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. -
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJul 11, 2018The c.5701G>C (p.E1901Q) alteration is located in exon 28 (coding exon 27) of the SCN5A gene. This alteration results from a G to C substitution at nucleotide position 5701, causing the glutamic acid (E) at amino acid position 1901 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Cardiac arrhythmia Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthJun 28, 2023- -
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: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
Pathogenic
0.67
CardioboostCm
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.29
D
BayesDel_noAF
Pathogenic
0.47
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.70
.;.;.;.;.;D;.;.;.
Eigen
Pathogenic
0.88
Eigen_PC
Pathogenic
0.80
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.95
.;D;D;D;D;D;D;.;D
M_CAP
Pathogenic
0.87
D
MetaRNN
Pathogenic
0.96
D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.8
.;.;.;.;.;H;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
0.70
T
PROVEAN
Uncertain
-2.8
D;D;D;D;D;D;D;D;D
REVEL
Pathogenic
0.95
Sift
Pathogenic
0.0
D;D;D;D;D;D;D;D;D
Sift4G
Benign
0.077
T;T;T;T;T;T;T;T;T
Polyphen
1.0
D;D;.;D;.;D;D;.;.
Vest4
0.84
MutPred
0.83
.;.;Gain of loop (P = 3e-04);.;.;Gain of loop (P = 3e-04);.;.;.;
MVP
0.98
MPC
1.4
ClinPred
0.99
D
GERP RS
4.9
Varity_R
0.86
gMVP
0.93

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: rs199473325; hg19: chr3-38592162; API