3-38581079-C-T

Variant names:

• chr3-38581079-C-T
• rs763891399
• NM_001099404.2:c.3080G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001099404.2(SCN5A):​c.3080G>A​(p.Arg1027Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000409 in 1,613,486 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1027W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000046 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11 B:1
• Conservation: PhyloP100: 1.13
• Publications: 6 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.22782767).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.3080G>A	p.Arg1027Gln	missense_variant	Exon 17 of 28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.3080G>A	p.Arg1027Gln	missense_variant	Exon 17 of 28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.3080G>A	p.Arg1027Gln	missense_variant	Exon 17 of 28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.3080G>A	p.Arg1027Gln	missense_variant	Exon 17 of 28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes AF: 0.0000461 AC: 7 AN: 151872 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000883

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000403 AC: 10 AN: 248354 AF XY: 0.0000445

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000623

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000404 AC: 59 AN: 1461614 Hom.: 0 Cov.: 37 AF XY: 0.0000468 AC XY: 34 AN XY: 727082

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

American (AMR) AF: 0.0000224 AC: 1 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000387 AC: 43 AN: 1111840

Other (OTH) AF: 0.0000497 AC: 3 AN: 60370

GnomAD4 genome AF: 0.0000461 AC: 7 AN: 151872 Hom.: 1 Cov.: 32 AF XY: 0.0000674 AC XY: 5 AN XY: 74182

African (AFR) AF: 0.00 AC: 0 AN: 41294

American (AMR) AF: 0.00 AC: 0 AN: 15274

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10562

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

European-Non Finnish (NFE) AF: 0.0000883 AC: 6 AN: 67978

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.000285 Hom.: 1

Bravo AF: 0.0000227

ExAC AF: 0.0000496 AC: 6

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4 Benign:1

Mar 03, 2015

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SCN5A: PM2

Clinical Genetics, Academic Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1027 of the SCN5A protein (p.Arg1027Gln). This variant is present in population databases (rs763891399, gnomAD 0.009%). This missense change has been observed in individual(s) with SCN5A-related conditions (PMID: 17210841, 25904541). ClinVar contains an entry for this variant (Variation ID: 520458). 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 disruptive. 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 Uncertain:2

Jun 22, 2016

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 18, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SCN5A c.3080G>A (p.Arg1027Gln) results in a conservative amino acid change located in the Sodium ion transport-associated domain (IPR010526) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 248354 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SCN5A causing Brugada Syndrome (4e-05 vs 0.00017), allowing no conclusion about variant significance. c.3080G>A has been reported in the literature in individuals affected with long-QT syndrome or restrictive cardiomyopathy, ventricular tachycardia and atrial fibrillation (Kapplinger_2015, Seidelmann_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Brugada Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22030895, 30143662, 25904541, 28087566, 20403459, 26746457, 17210841). ClinVar contains an entry for this variant (Variation ID: 520458). Based on the evidence outlined above, the variant was classified as uncertain significance.

Cardiac arrhythmia Uncertain:2

Jan 17, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with glutamine at codon 1027 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Brugada syndrome or long QT syndrome (PMID: 1309946, 25904541). This variant has been identified in 14/276396 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.

Sep 23, 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 arginine with glutamine at codon 1027 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Brugada syndrome or long QT syndrome (PMID: 1309946, 25904541). This variant has been identified in 14/276396 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.

Dilated cardiomyopathy 1E Uncertain:1

Jul 17, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.2, this variant is classified as VUS 3C. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene (PMID: 29806494). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine (exon 17). (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD at a frequency of 0.005% for a dominant condition (14 heterozygotes, 1 homozygote). (SP) 0309 - Alternative amino acid changes at the same position have been observed in gnomAD: p.(Arg1027Trp): 0.0004% (1 heterozygote, 0 homozygote); p.(Arg1027Pro): 0.0004% (1 heterozygote, 0 homozygote). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. Minor amino acid change, moderate conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. Located in DII/DIII intracellular linker region. (I) 0710 - Another variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. p.(Arg1027Trp): ClinVar VUS x1 (Brugada syndrome), PMID: 24981977: one patient with ARVC, PMID: 29544605, one SIDS patient who also had a truncating CSRP3 variant. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. ClinVar: VUS x3 (one Brugada syndrome, two entries with no clinical information), LOVD3: VUS x2. PMID: 25904541: one patient with LQTS; PMID: 28521022: A review paper that refers to this variant as having unknown significance. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1010 - Functional evidence for this variant is inconclusive. Several studies have used the hH1 construct/SCN5A clone that contains this variant to test the functionality of other SCN5A variants, and results suggested that it is associated with a negative shift of steady state inactivation and slower channel recovery. However, the functional effect of this variant alone is unknown (PMID: 14500339, PMID: 16632547, PMID: 30143662). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting Pathogenic, (I) – Information, (SB) – Supporting Benign

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

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cardiovascular phenotype Uncertain:1

Jan 28, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R1027Q variant (also known as c.3080G>A), located in coding exon 16 of the SCN5A gene, results from a G to A substitution at nucleotide position 3080. The arginine at codon 1027 is replaced by glutamine, an amino acid with highly similar properties. This variant has been reported in an individual with restricted cardiomyopathy and arrhythmias, who also had a co-occurring variant in TNNT2 (Seidelmann SB et al. Circ Cardiovasc Genet, 2017 Feb;10:[Epub ahead of print]). This variant was also detected in one individual from a long QT cohort; however, functional studies were reportedly normal, and clinical details were limited (Kapplinger JD et al. Circ Cardiovasc Genet, 2015 Aug;8:582-95). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
CardioboostArm	Benign	0.0000059
CardioboostCm	Benign	0.0011
BayesDel_addAF	Benign	-0.031	T
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0	.;.;.;.;.;T;.;.;.
Eigen	Benign	-0.000069
Eigen_PC	Benign	-0.065
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.0	.;D;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Benign	0.23	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	0.0	.;L;.;.;.;L;.;.;.
PhyloP100		1.1
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.92	N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.38
Sift	Benign	0.57	T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.63	T;T;T;T;T;T;T;T;T
Vest4		0.35
ClinPred		0.14	T
GERP RS		5.1
Varity_R		0.090
gMVP		0.57
Mutation Taster		=94/6	polymorphism

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: rs763891399; hg19: chr3-38622570;