3-38566558-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP2PP5

The NM_000335.5(SCN5A):c.3688G>A(p.Glu1230Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,612 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

SCN5A
NM_000335.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.327

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 6 ACMG points.

PM1

In a topological_domain Extracellular (size 12) in uniprot entity SCN5A_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_000335.5

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.

PP5

Variant 3-38566558-C-T is Pathogenic according to our data. Variant chr3-38566558-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67812.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, not_provided=1}. Variant chr3-38566558-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2 link	c.3691G>A	p.Glu1231Lys	missense_variant	Exon 21 of 28	ENST00000413689.6	NP_001092874.1	Q14524H9KVD2
SCN5A	NM_000335.5 link	c.3688G>A	p.Glu1230Lys	missense_variant	Exon 21 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.3691G>A	p.Glu1231Lys	missense_variant	Exon 21 of 28	5	NM_001099404.2	ENSP00000410257.1		H9KVD2
SCN5A	ENST00000423572.7 link	c.3688G>A	p.Glu1230Lys	missense_variant	Exon 21 of 28	1	NM_000335.5	ENSP00000398266.2		Q14524-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250008

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135484

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461612

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727102

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:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Dec 06, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1231 of the SCN5A protein (p.Glu1231Lys). This variant is present in population databases (rs199473598, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of SCN5A-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 67812). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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. -

Nov 11, 2011

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Glu1231Lys in the SCN5A gene; disease-causing mutation (Tester D et al. 2008). TheG>A nucleotide substitution in exon 21 of the SCN5A gene, results in replacement of the normal Glutamic acid codon (GAG) with a Lysine codon (AAG) at amino acid position 1231 in the cardiac sodium voltage-gated channel, type V-a. This missense change is denoted p.Glu1231Lys (aka E1231K) at the protein level and c.3691 G>A at the cDNA level. The Glu1231Lys mutation has been reported in association with LQTS (Tester D et al. 2008). Tester et al. reported Glu1231Lys in one patient with LQTS and did not observe it in more than 1,500 control alleles. This mutation also was not observed in up to 400 control alleles from individuals of African American and Caucasian ancestry tested at GeneDx, indicating it is not a common benign polymorphsim. Glu1231Lys results in a non-conservative amino acid substitution of a negatively charged Glutamic acid with a positively charged Lysine residue at a position that is class conserved. Furthermore, mutations in surrounding codons (Tyr1228His, Arg1232Gln, Lys1236Arg, Lys1236Asn, Leu1239Pro) have been reported in association with Brugada syndrome, further supporting the functional importance of this region of the protein. The variant is found in LQT panel(s). -

Congenital long QT 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 Long QT syndrome in the following publications (PMID:15840476). 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

0.093

CardioboostCm

Benign

0.0093

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Pathogenic

0.15

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.81

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

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.070

FATHMM_MKL

Uncertain

0.76

LIST_S2

Uncertain

0.92

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

M_CAP

Uncertain

0.16

MetaRNN

Uncertain

0.51

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

MetaSVM

Uncertain

0.59

MutationAssessor

Benign

-0.025

.;.;.;.;.;N;.;.;.

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.1

N;N;N;N;N;N;N;N;N

REVEL

Uncertain

0.55

Sift

Benign

0.11

T;T;T;T;T;T;T;T;T

Sift4G

Benign

0.37

T;T;T;T;T;T;T;T;T

Polyphen

0.021

B;B;.;B;.;B;B;.;.

Vest4

0.78

MutPred

0.82

Gain of methylation at E1231 (P = 0.0193);.;Gain of methylation at E1231 (P = 0.0193);Gain of methylation at E1231 (P = 0.0193);.;Gain of methylation at E1231 (P = 0.0193);.;.;.;

MVP

0.96

MPC

0.62

ClinPred

0.44

GERP RS

4.5

Varity_R

0.34

gMVP

0.84

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