rs199473320

chr3-38550878-G-Cchr3-38550878-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001099404.2(SCN5A):c.5494C>G(p.Gln1832Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000867 in 1,613,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q1832K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000054 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:4 O:1
• Conservation: PhyloP100: 4.72

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SCN5A
• BP4: Computational evidence support a benign effect (MetaRNN=0.14536268).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.5494C>G	p.Gln1832Glu	missense_variant	28/28	ENST00000413689.6
SCN5A	NM_000335.5	c.5491C>G	p.Gln1831Glu	missense_variant	28/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.5494C>G	p.Gln1832Glu	missense_variant	28/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.5491C>G	p.Gln1831Glu	missense_variant	28/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 152152 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00135

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: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000601 AC: 15 AN: 249442 Hom.: 0 AF XY: 0.0000370 AC XY: 5 AN XY: 135300

Gnomad AFR exome AF: 0.000709

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: 0.0000265

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000540 AC: 79 AN: 1461610 Hom.: 0 Cov.: 32 AF XY: 0.0000591 AC XY: 43 AN XY: 727092

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000279

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.000401 AC: 61 AN: 152270 Hom.: 0 Cov.: 33 AF XY: 0.000376 AC XY: 28 AN XY: 74454

Gnomad4 AFR AF: 0.00140

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: 0.0000294

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.000302

ESP6500AA AF: 0.000702 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000743 AC: 9

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:4 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 10, 2020	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 04, 2020	This variant is associated with the following publications: (PMID: 31983221, 30193851, 20129283, 28370132, 23861362, 29728395, 24631775, 25119684, 16521247, 23414114, 22840528) -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 11, 2024	- -

Brugada syndrome Benign:1 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 Brugada syndrome in the following publications (PMID:16521247;PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 03, 2015

The p.Gln1832Glu variant in SCN5A has been reported in 2 individuals with Brugad a syndrome, 1 infant with sudden death, and 1 individual with focal epilepsy (Ar bustini 2005, Kapplinger 2010, Partemi 2015, Morganstein 2015). The variant has also been identified by our laboratory in 1 adult and 1 infant with DCM, and 1 i ndividual with VT. In vitro functional studies provide some evidence that the p. Gln1832Glu variant may impact protein function (Morganstein 2015), although thes e types of assays may not accurately represent biological function. The p.Gln183 2Glu variant has also been identified in 0.1% (8/9806) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP r s199473320). The affected amino acid is not well conserved in evolution, raising the possibility that a change may be tolerated. Other computational prediction tools do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Gln1832Glu variant is uncertain. -

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Jul 29, 2016

- -

Cardiac arrhythmia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Dec 16, 2022

This missense variant replaces glutamine with glutamic acid at codon 1832 of the SCN5A protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. An experimental functional study has shown that this variant may impact sodium channel function due to protein trafficking defects (PMID: 28370132). This variant has been reported in three individuals affected with or suspected of having Brugada syndrome (PMID: 20129283, 32893267, 36291626, in an infant affected with sudden death who also carried SCN5A p.Arg1944* variant (PMID: 24631775), and in an individual affected with epilepsy (PMID: 25119684). This variant has also been identified in 28/280826 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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. -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 24, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
CardioboostArm	Benign	0.0020
CardioboostCm	Uncertain	0.23
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.010
Cadd	Benign	23
Dann	Uncertain	0.99
Eigen	Benign	0.063
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Benign	0.15	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.48	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.87	N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.53
Sift	Uncertain	0.0070	D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.022	D;D;D;D;D;D;D;D;D
Polyphen		0.76	P;B;.;P;.;P;B;.;.
Vest4		0.17
MVP		0.62
MPC		0.85
ClinPred		0.074	T
GERP RS		4.8
Varity_R		0.39
gMVP		0.96

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

Other links and lift over

dbSNP: rs199473320; hg19: chr3-38592369;