chr3-38562485-G-A

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP2PP3_StrongPP5

The NM_000335.5(SCN5A):c.3890C>T(p.Pro1297Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,613,680 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: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

SCN5A
NM_000335.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:2O:1

Conservation

PhyloP100: 10.0

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 8 ACMG points.

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, 0.982

PP5

Variant 3-38562485-G-A is Pathogenic according to our data. Variant chr3-38562485-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 9394.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1, not_provided=1}. Variant chr3-38562485-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2 link	c.3893C>T	p.Pro1298Leu	missense_variant	Exon 22 of 28	ENST00000413689.6	NP_001092874.1	Q14524H9KVD2
SCN5A	NM_000335.5 link	c.3890C>T	p.Pro1297Leu	missense_variant	Exon 22 of 28	ENST00000423572.7	NP_000326.2	Q14524-2Q86V90

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6 link	c.3893C>T	p.Pro1298Leu	missense_variant	Exon 22 of 28	5	NM_001099404.2	ENSP00000410257.1		H9KVD2
SCN5A	ENST00000423572.7 link	c.3890C>T	p.Pro1297Leu	missense_variant	Exon 22 of 28	1	NM_000335.5	ENSP00000398266.2		Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152170

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:

0.0000178

AC:

AN:

1461510

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

727032

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000225

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74326

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

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cardiac arrhythmia

Uncertain:2

Sep 23, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 10, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the transmembrane domain DIII of the SCN5A protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. Experimental studies have shown that this variant may alter sodium channel kinetics (PMID: 20384651, 20448214, 20539757). However, clinical significance of these observations is not clear. This variant has been reported in compound heterozygosity with a pathogenic p.Gly1408Arg variant in three siblings affected with congenital sick sinus syndrome (PMID: 14523039). Eleven heterozygous carriers of this variant were asymptomatic and largely without electrocardiographic abnormalities, except the proband's maternal grandmother, who had first-degree heart block. In this family, heterozygous p.Gly1408Arg variant segregated with first-degree heart block phenotype in multiple individuals. This variant is rare in the general population and has been identified in 0/277264 chromosomes by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, additional studies are necessary to determine the pathogenicity of this variant conclusively. Medical management should be considered based on personal and family history. -

Dilated cardiomyopathy 1E;C1859062:Long QT syndrome 3;C4551804:Brugada syndrome 1

Pathogenic:1

Aug 16, 2024

Institute of Human Genetics, Heidelberg University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sick sinus syndrome 1

Pathogenic:1

Oct 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sick sinus 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 Sick sinus syndrome in the following publications (PMID:14523039;PMID:20384651;PMID:20448214;PMID:20539757). 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

0.34

CardioboostCm

Uncertain

0.39

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

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

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

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

M_CAP

Pathogenic

0.85

MetaRNN

Pathogenic

0.98

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.1

.;.;.;.;.;M;.;.;.

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-4.1

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

REVEL

Pathogenic

0.92

Sift

Uncertain

0.010

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

Sift4G

Uncertain

0.0090

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

Polyphen

0.99

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

Vest4

0.93

MutPred

0.84

Gain of MoRF binding (P = 0.057);.;Gain of MoRF binding (P = 0.057);Gain of MoRF binding (P = 0.057);.;Gain of MoRF binding (P = 0.057);.;.;.;

MVP

0.96

MPC

1.5

ClinPred

0.99

GERP RS

4.0

Varity_R

0.53

gMVP

0.97

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