3-38605956-G-C

Position:

chr3-38605956-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_000335.5(SCN5A):c.1333C>G(p.His445Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000128 in 1,604,710 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. H445H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

SCN5A
NM_000335.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:7O:1

Conservation

PhyloP100: 6.68

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 3 ACMG points.

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2 link	c.1333C>G	p.His445Asp	missense_variant	10/28	ENST00000413689.6	NP_001092874.1	Q14524H9KVD2
SCN5A	NM_000335.5 link	c.1333C>G	p.His445Asp	missense_variant	10/28	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.1333C>G	p.His445Asp	missense_variant	10/28	5	NM_001099404.2	ENSP00000410257.1		H9KVD2
SCN5A	ENST00000423572.7 link	c.1333C>G	p.His445Asp	missense_variant	10/28	1	NM_000335.5	ENSP00000398266.2		Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000533

AC:

AN:

243840

Hom.:

AF XY:

0.0000378

AC XY:

AN XY:

132114

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000294

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000472

Gnomad NFE exome

AF:

0.0000904

Gnomad OTH exome

AF:

0.000169

GnomAD4 exome

AF:

0.000129

AC:

188

AN:

1452388

Hom.:

Cov.:

AF XY:

0.000112

AC XY:

AN XY:

721306

show subpopulations

Gnomad4 AFR exome

AF:

0.0000603

Gnomad4 AMR exome

AF:

0.0000679

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.000153

Gnomad4 OTH exome

AF:

0.000183

GnomAD4 genome

AF:

0.000112

AC:

AN:

152322

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000139

Hom.:

Bravo

AF:

0.000132

ExAC

AF:

0.0000496

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Brugada syndrome 1

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0103 - Loss of function and gain of function are both known mechanisms of disease in this gene. Loss of function is usually associated with Brugada syndrome 1 (MIM#601144) and sick sinus syndrome 1 (SSS) (MIM#608567), whereas gain of function is usually associated with long QT syndrome-3 (LQTS) (MIM#603830). Dilated cardiomyopathy 1E (DCM) (MIM#601154) can be caused by variants with either a loss or gain of function mechanism (PMID: 29798782). (I) 0108 - This gene is associated with both recessive and dominant disease. Most conditions associated with this gene are dominantly inherited; however SSS is caused by biallelic variants (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from histidine to aspartic acid. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (17 heterozygotes, 0 homozygotes). (SP) 0309 - Alternative amino acid changes at the same position has been observed in gnomAD (v2) (3 heterozygotes, 0 homozygote). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated DI to DII intracellular linker domain (UniProt). (I) 0710 - Other missense variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. The p.(His445Gln) and p.(His445Tyr) variants have each been reported once as a VUS in ClinVar. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has previously been reported in individuals with Brugada syndrome, atrial fibrillation, and sudden infant death syndrome (SIDS), and has been classified as both a VUS and potentially disease causing (PMID: 30193851, PMID: 25650408, PMID: 18378609, PMID: 30086531, ClinVar). (I) 0903 - This variant has limited evidence for segregation with disease. This variant has been shown to segregate with atrial fibrillation in a proband and two affected family members. Additionally, the variant was absent from an unaffected family member (PMID: 18378609). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 26, 2020	Identified in patients with LQTS, atrial fibrillation, Brugada syndrome, or sudden infant death either tested at GeneDx or in the published literature (Darbar et al., 2008; Le Scouarnec et al., 2015; Campuzano et al., 2018); however, some individuals harbor additional variants that could explain their phenotype; Observed to segregate with atrial fibrillation in one proband's affected father and brother (Darbar et al., 2008); In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 30046; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 19808477, 22581653, 25650408, 18378609, 28150151, 30086531, 28086167, 30193851) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 26, 2024	This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 445 of the SCN5A protein (p.His445Asp). This variant is present in population databases (rs199473112, gnomAD 0.008%). This missense change has been observed in individual(s) with Brugada syndrome, dilated cardiomyopathy, or atrial fibrillation (PMID: 18378609, 19808477, 25650408, 30193851, 37652022). ClinVar contains an entry for this variant (Variation ID: 30046). 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 tolerated. This variant disrupts the p.His445 amino acid residue in SCN5A. Other variant(s) that disrupt this residue have been observed in individuals with SCN5A-related conditions (internal data), which suggests that this may be a clinically significant amino acid residue. 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. -

Atrial fibrillation, familial, 10

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 15, 2008

- -

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 submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 14, 2022

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 27, 2024

The p.H445D variant (also known as c.1333C>G), located in coding exon 9 of the SCN5A gene, results from a C to G substitution at nucleotide position 1333. The histidine at codon 445 is replaced by aspartic acid, an amino acid with similar properties. This variant has been detected in individuals from various cohorts including sudden infant death, sudden death, arrhythmia, and Brugada syndrome; however, clinical details were limited, some reports may overlap, and additional variants in were also detected in some cases (Le Scouarnec S et al. Hum Mol Genet, 2015 May;24:2757-63; Campuzano O et al. Forensic Sci Int, 2017 Feb;271:120-125; Amin AS et al. Int J Cardiol, 2018 Sep;266:128-132; Campuzano O et al. Forensic Sci Int Genet, 2018 11;37:54-63; Berthome P et al. Heart Rhythm, 2019 02;16:260-267). This variant has also been reported in association with atrial fibrillation and, in one family, was detected in three affected individuals (Darbar D et al. Circulation, 2008 Apr;117:1927-35; Watanabe H et al. Circ Arrhythm Electrophysiol, 2009 Jun;2:268-75). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Cardiac arrhythmia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

May 15, 2023

This missense variant replaces histidine with aspartic acid at codon 445 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that this variant alters voltage-dependence of activation, recovery and inactivation of the sodium channel (Gillani et al., 2010). This variant has been reported in individuals affected with atrial fibrillation (PMID: 18378609, 19808477), Brugada syndrome (PMID: 25650408, 30193851, 32893267), dilated cardiomyopathy (PMID: 32826072), and sudden death in infancy (PMID: 30086531). This variant has also been identified in 14/275240 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Atrial fibrillation

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 Atrial fibrillation in the following publications (PMID:18378609). 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

Uncertain

0.37

CardioboostCm

Benign

0.0020

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.22

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.48

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

Eigen

Benign

0.067

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

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

M_CAP

Uncertain

0.27

MetaRNN

Uncertain

0.55

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

MetaSVM

Uncertain

0.35

MutationAssessor

Benign

0.20

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

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.4

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

REVEL

Uncertain

0.63

Sift

Uncertain

0.013

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

Sift4G

Benign

0.079

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

Polyphen

0.011

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

Vest4

0.57

MutPred

0.75

Loss of MoRF binding (P = 0.0487);Loss of MoRF binding (P = 0.0487);Loss of MoRF binding (P = 0.0487);Loss of MoRF binding (P = 0.0487);Loss of MoRF binding (P = 0.0487);Loss of MoRF binding (P = 0.0487);Loss of MoRF binding (P = 0.0487);Loss of MoRF binding (P = 0.0487);Loss of MoRF binding (P = 0.0487);

MVP

0.88

MPC

0.61

ClinPred

0.13

GERP RS

5.5

Varity_R

0.21

gMVP

0.72

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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