3-38604064-C-T

Position:

chr3-38604064-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 5P and 3B. PM1PM2PP2BP4_ModerateBP6

The NM_000335.5(SCN5A):c.1538G>A(p.Arg513His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000561 in 1,603,938 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

SCN5A
NM_000335.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 0.0690

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 Uncertain_significance. Variant got 2 ACMG points.

PM1

In a modified_residue Omega-N-methylarginine; alternate (size 0) in uniprot entity SCN5A_HUMAN

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: 4.8279 (greater than threshold 3.09). The gene has 99 curated pathogenic missense variants (we use a threshold of 10). The gene has 60 curated benign missense variants. GenCC has associacion of the 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.09594175).

BP6

Variant 3-38604064-C-T is Benign according to our data. Variant chr3-38604064-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48285.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2 link	c.1538G>A	p.Arg513His	missense_variant	12/28	ENST00000413689.6	NP_001092874.1	Q14524H9KVD2
SCN5A	NM_000335.5 link	c.1538G>A	p.Arg513His	missense_variant	12/28	ENST00000423572.7	NP_000326.2	Q14524-2Q86V90

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6 link	c.1538G>A	p.Arg513His	missense_variant	12/28	5	NM_001099404.2	ENSP00000410257.1		H9KVD2
SCN5A	ENST00000423572.7 link	c.1538G>A	p.Arg513His	missense_variant	12/28	1	NM_000335.5	ENSP00000398266.2		Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00000433

AC:

AN:

230892

Hom.:

AF XY:

0.00

AC XY:

AN XY:

125096

show subpopulations

Gnomad AFR exome

AF:

0.0000736

Gnomad AMR exome

AF:

0.00

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:

0.00000482

AC:

AN:

1451762

Hom.:

Cov.:

AF XY:

0.00000555

AC XY:

AN XY:

721138

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000119

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000452

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000264

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

SCN5A-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 20, 2023

The SCN5A c.1538G>A variant is predicted to result in the amino acid substitution p.Arg513His. This variant was reported in an individual with sudden unexplained nocturnal death syndrome (Liu et al 2014. PubMed ID: 24529773). This variant was also reported in an individual with cardiomyopathy (Priganc et al 2016. PubMed ID: 27554632). This variant is reported in 0.0074% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-38645555-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 04, 2023

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 513 of the SCN5A protein (p.Arg513His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with sudden unexplained nocturnal death syndrome and dilated cardiomyopathy (PMID: 24529773, 27554632). ClinVar contains an entry for this variant (Variation ID: 48285). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The histidine 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. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 28, 2012

Arg513His in exon 12 of SCN5A: This variant is not expected to have clinical sig nificance due to a lack of conservation across species, including primates and o ther mammals. Of note, all other primates (chimp, gorilla, orangutan, and others ) have a histidine (His) at this position despite high nearby amino acid conserv ation. A disease modifying role of this variant cannot be excluded. -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 20, 2023

This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Cardiac arrhythmia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Dec 11, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

CardioboostCm

Benign

0.0028

BayesDel_addAF

Uncertain

0.043

BayesDel_noAF

Benign

-0.18

CADD

Benign

9.8

DANN

Benign

0.69

DEOGEN2

Uncertain

0.45

.;.;.;.;.;T;.;.;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0027

LIST_S2

Benign

0.10

.;T;T;T;T;T;T;.;T

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.096

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

MetaSVM

Benign

-0.51

MutationAssessor

Benign

0.69

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

PrimateAI

Benign

0.31

PROVEAN

Benign

0.64

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

REVEL

Uncertain

0.45

Sift

Benign

0.21

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

Sift4G

Benign

0.16

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

Polyphen

0.0

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

Vest4

0.10

MutPred

0.33

Loss of MoRF binding (P = 0.027);Loss of MoRF binding (P = 0.027);Loss of MoRF binding (P = 0.027);Loss of MoRF binding (P = 0.027);Loss of MoRF binding (P = 0.027);Loss of MoRF binding (P = 0.027);Loss of MoRF binding (P = 0.027);Loss of MoRF binding (P = 0.027);Loss of MoRF binding (P = 0.027);

MVP

0.87

MPC

0.43

ClinPred

0.040

GERP RS

1.3

Varity_R

0.030

gMVP

0.52

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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