rs199473265

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP2PP3_Moderate

The NM_001099404.2(SCN5A):c.4500G>T(p.Lys1500Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 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 (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

SCN5A
NM_001099404.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3O:1

Conservation

PhyloP100: 1.31

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]

SCN5A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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_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, 0.852

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2 linkuse as main transcript	c.4500G>T	p.Lys1500Asn	missense_variant	26/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5 linkuse as main transcript	c.4497G>T	p.Lys1499Asn	missense_variant	26/28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6 linkuse as main transcript	c.4500G>T	p.Lys1500Asn	missense_variant	26/28	5	NM_001099404.2	ENSP00000410257	P4
SCN5A	ENST00000423572.7 linkuse as main transcript	c.4497G>T	p.Lys1499Asn	missense_variant	26/28	1	NM_000335.5	ENSP00000398266	A1	Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152130

Hom.:

Cov.:

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461756

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727196

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152130

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74310

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3Other: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	Oct 12, 2023	This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 1500 of the SCN5A protein (p.Lys1500Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Long QT syndrome (PMID: 10508990). ClinVar contains an entry for this variant (Variation ID: 67903). 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. 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	AiLife Diagnostics, AiLife Diagnostics	Sep 21, 2021	- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 05, 2023

The p.K1500N variant (also known as c.4500G>T), located in coding exon 25 of the SCN5A gene, results from a G to T substitution at nucleotide position 4500. The lysine at codon 1500 is replaced by asparagine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Congenital long QT 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 Long QT syndrome in the following publications (PMID:10508990;PMID:15120823). 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

0.99

CardioboostCm

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

.;.;.;.;.;D;.;.;.

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.97

.;D;D;D;D;D;D;.;D

M_CAP

Pathogenic

0.86

MetaRNN

Pathogenic

0.85

D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.3

.;.;.;.;.;H;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;D

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-4.5

D;D;D;D;D;D;D;D;D

REVEL

Pathogenic

0.72

Sift

Pathogenic

0.0

D;D;D;D;D;D;D;D;D

Sift4G

Uncertain

0.0090

D;D;D;D;D;D;D;D;D

Polyphen

1.0

D;P;.;D;.;D;D;.;.

Vest4

0.76

MutPred

0.20

.;.;Loss of MoRF binding (P = 0.0352);.;.;Loss of MoRF binding (P = 0.0352);.;.;.;

MVP

0.97

MPC

1.6

ClinPred

1.0

GERP RS

4.5

Varity_R

0.97

gMVP

0.95

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over