3-38609803-C-T

Variant names:

• chr3-38609803-C-T
• rs199473084
• NM_001099404.2:c.865G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM1 BP4_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. 14/24 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G289D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7 O:1
• Conservation: PhyloP100: 2.35
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• Brugada syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Brugada syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Laboratory for Molecular Medicine, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1E

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial long QT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• long QT syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• sick sinus syndrome 1

  Inheritance: AD, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• progressive familial heart block, type 1A

  Inheritance: SD, AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp
• atrial standstill

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial sick sinus syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• paroxysmal familial ventricular fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• progressive familial heart block

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• short QT syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 22 uncertain in NM_001099404.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.16974679).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001099404.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN5A	NM_001099404.2	MANE Plus Clinical	c.865G>A	p.Gly289Ser	missense	Exon 7 of 28	NP_001092874.1
	SCN5A	NM_000335.5	MANE Select	c.865G>A	p.Gly289Ser	missense	Exon 7 of 28	NP_000326.2
	SCN5A	NM_198056.3		c.865G>A	p.Gly289Ser	missense	Exon 7 of 28	NP_932173.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN5A	ENST00000413689.6	TSL:5 MANE Plus Clinical	c.865G>A	p.Gly289Ser	missense	Exon 7 of 28	ENSP00000410257.1
	SCN5A	ENST00000423572.7	TSL:1 MANE Select	c.865G>A	p.Gly289Ser	missense	Exon 7 of 28	ENSP00000398266.2
	SCN5A	ENST00000333535.9	TSL:1	c.865G>A	p.Gly289Ser	missense	Exon 7 of 28	ENSP00000328968.4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152250 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.0000161 AC: 4 AN: 249170 AF XY: 0.00000740

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000192 AC: 28 AN: 1461510 Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 16 AN XY: 727056

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53222

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000189 AC: 21 AN: 1111858

Other (OTH) AF: 0.0000166 AC: 1 AN: 60370

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152250 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74370

African (AFR) AF: 0.0000482 AC: 2 AN: 41464

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000134 Hom.: 0

Bravo AF: 0.00000756

ESP6500AA AF: 0.000232 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Dec 04, 2017

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: provider interpretation

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 “enhanced classification” 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.

Sep 07, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 22, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Feb 13, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Aug 31, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

Cardiovascular phenotype Uncertain:1

Feb 21, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

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: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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
CardioboostArm	Benign	0.000012
CardioboostCm	Benign	0.0056
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Uncertain	0.030
CADD	Benign	15
DANN	Benign	0.91
DEOGEN2	Uncertain	0.60	D
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	0.18	N
PhyloP100		2.3
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.20	N
REVEL	Uncertain	0.52
Sift	Benign	0.55	T
Sift4G	Benign	0.95	T
Polyphen		0.0020	B
Vest4		0.68
MVP		0.93
MPC		0.36
ClinPred		0.073	T
GERP RS		5.1
Varity_R		0.085
gMVP		0.87
Mutation Taster		=0/100	disease causing

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

Other links and lift over

dbSNP: rs199473084; hg19: chr3-38651294; COSMIC: COSV100348801; COSMIC: COSV100348801;