chr3-38609803-C-T

Position:

chr3-38609803-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_001099404.2(SCN5A):c.865G>A(p.Gly289Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,613,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

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

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

SCN5A
NM_001099404.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.35

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 1 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 4.7729 (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.

BP4

Computational evidence support a benign effect (MetaRNN=0.16974679).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2 linkuse as main transcript	c.865G>A	p.Gly289Ser	missense_variant	7/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5 linkuse as main transcript	c.865G>A	p.Gly289Ser	missense_variant	7/28	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.865G>A	p.Gly289Ser	missense_variant	7/28	5	NM_001099404.2	ENSP00000410257	P4
SCN5A	ENST00000423572.7 linkuse as main transcript	c.865G>A	p.Gly289Ser	missense_variant	7/28	1	NM_000335.5	ENSP00000398266	A1	Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000161

AC:

AN:

249170

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135176

show subpopulations

Gnomad AFR exome

AF:

0.000129

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:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1461510

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

727056

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000189

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152250

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.0000482

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000151

Hom.:

Bravo

AF:

0.00000756

ESP6500AA

AF:

0.000232

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Dec 04, 2017	p.Gly289Ser (G289S; c.865G>A) in exon 7 of the SCN5A gene Chromosome location 3:38651294 C / T Based on the lack of case data, the variability of this residue across species, and presence of this variant in gnomAD, we classify it as a VUS. This variant has not previously been reported in a clinically-confirmed case of LQTS or Brugada syndrome. Our patient does not have a clear clinical diagnosis either. Hata et al. (2017) reported this variant in the SUD case of a 28-year-old Japanese woman who was found in a hot bath with autopsy evidence of drowning and alcohol detected on blood toxicology. This variant was also reported by Kapplinger et al. (2009) in one patient tested for LQTS at Familion. (This is most likely our patient, as medical records indicate that her LQTS testing was sent to Familion.) However, in a 2015 paper by the same group involving â€œenhanced classificationâ€ of SCN5A variants, p.Gly289Ser is listed as having been found in 0 LQTS patients, 0 Brugada patients, and 1 control (out of 8975). All 7 in silico prediction models used for this later study predicted the variant to be benign. This is a nonconservative amino acid change, resulting in the replacement of a nonpolar glycine with a polar serine. The Glycine at location 289 is poorly conserved across species. In fact, Serine is the default amino acid in at least one mammalian species and in several species of bird and reptile. According to Kapplinger et al. (2009), this codon is in the DI-S5/S6 region of the protein. There are no Likely Pathogenic or Pathogenic variants listed in ClinVar within 5 amino acids to either side, indicating that this region of the protein might be tolerant of change. This variant was reported in 4 individuals in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Specifically, the variant was observed in 2 African-ancestry (MAF 0.013%) and 2 non-Finnish European-ancestry individuals (MAF 0.0018%) in the gnomAD database. Overall MAF 0.0016%. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 07, 2021	Reported in association with LQTS and sudden unexplained death (SUD) in published literature (Kapplinger et al., 2009; Hata et al., 2017); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32268277, 28469501, 19716085, 25637381, 22581653) -

Cardiac arrhythmia

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 15, 2023	This missense variant replaces glycine with serine at codon 289 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual referred for long QT syndrome genetic test (PMID:19716085) and in an individual affected with sudden death (PMID: 28469501). This variant has been identified in 4/249170 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 22, 2021	This missense variant replaces glycine with serine at codon 289 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual referred for long QT syndrome genetic test (PMID:19716085) and in an individual affected with sudden death (PMID: 28469501). This variant has been identified in 4/249170 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. -

Brugada syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 31, 2022

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 289 of the SCN5A protein (p.Gly289Ser). This variant is present in population databases (rs199473084, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of SCN5A-related conditions (PMID: 19716085, 28469501). ClinVar contains an entry for this variant (Variation ID: 68050). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -

Long QT syndrome

Uncertain:1

Uncertain significance, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 21, 2021

The c.865G>A (p.G289S) alteration is located in exon 7 (coding exon 6) of the SCN5A gene. This alteration results from a G to A substitution at nucleotide position 865, causing the glycine (G) at amino acid position 289 to be replaced by a serine (S). Based on insufficient or conflicting evidence, 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:19716085). 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

0.073

CardioboostCm

Benign

0.0056

BayesDel_addAF

Uncertain

0.019

BayesDel_noAF

Uncertain

0.030

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Uncertain

0.60

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

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.83

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

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.17

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

MetaSVM

Benign

-0.37

MutationAssessor

Benign

0.18

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

MutationTaster

Benign

1.0

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

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.20

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

REVEL

Uncertain

0.52

Sift

Benign

0.55

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

Sift4G

Benign

0.95

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

Polyphen

0.0020

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

Vest4

0.68

MVP

0.93

MPC

0.36

ClinPred

0.073

GERP RS

5.1

Varity_R

0.085

gMVP

0.87

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