rs45489199

chr3-38550356-G-Cchr3-38550356-G-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_001099404.2(SCN5A):c.6016C>G(p.Pro2006Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 1,534,806 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. P2006R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (1 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:15 O:1
• Conservation: PhyloP100: -0.0910

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 Likely_benign. 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=0.010572314).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.6016C>G	p.Pro2006Ala	missense_variant	28/28	ENST00000413689.6
SCN5A	NM_000335.5	c.6013C>G	p.Pro2005Ala	missense_variant	28/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.6016C>G	p.Pro2006Ala	missense_variant	28/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.6013C>G	p.Pro2005Ala	missense_variant	28/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes AF: 0.00106 AC: 159 AN: 149550 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000199

Gnomad ASJ AF: 0.000292

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00228

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00182

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00109 AC: 214 AN: 195458 Hom.: 1 AF XY: 0.00114 AC XY: 118 AN XY: 103068

Gnomad AFR exome AF: 0.000201

Gnomad AMR exome AF: 0.000110

Gnomad ASJ exome AF: 0.000411

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000111

Gnomad FIN exome AF: 0.00139

Gnomad NFE exome AF: 0.00192

Gnomad OTH exome AF: 0.000881

GnomAD4 exome AF: 0.00125 AC: 1725 AN: 1385136 Hom.: 1 Cov.: 31 AF XY: 0.00122 AC XY: 826 AN XY: 678678

Gnomad4 AFR exome AF: 0.000127

Gnomad4 AMR exome AF: 0.000247

Gnomad4 ASJ exome AF: 0.000189

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000949

Gnomad4 FIN exome AF: 0.00125

Gnomad4 NFE exome AF: 0.00148

Gnomad4 OTH exome AF: 0.000808

GnomAD4 genome AF: 0.00106 AC: 159 AN: 149670 Hom.: 0 Cov.: 33 AF XY: 0.00102 AC XY: 75 AN XY: 73196

Gnomad4 AFR AF: 0.000221

Gnomad4 AMR AF: 0.000199

Gnomad4 ASJ AF: 0.000292

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00228

Gnomad4 NFE AF: 0.00182

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00141 Hom.: 0

Bravo AF: 0.000846

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000249 AC: 1

ESP6500EA AF: 0.00155 AC: 13

ExAC AF: 0.00123 AC: 146

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:15 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4 Other:1

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 20, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2020	This variant is associated with the following publications: (PMID: 22378279, 22360817, 21215473, 19597050, 26749013, 20875080, 2107088, 23714088, 27153395, 28988457, 10961955, 23631430, 23465283, 21070882, 17210839, 17210841, 15851227, 21410720, 21109022, 26159999, 23571586, 20129283, 29032884, 28831623, 28807990, 28798025, 16712702, 16379539, 19841300, 25351510, 26746457, 28301460, 29728395, 29672598, 30762279, 31337358, 31043699, 32880476) -
not provided, no classification provided	literature only	Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	-	This variant has been reported in the following publications (PMID:10961955;PMID:15851227;PMID:16379539;PMID:16712702;PMID:17210839;PMID:19841300;PMID:19597050;PMID:21109022;PMID:21410720;PMID:21070882;PMID:20129283). -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	SCN5A: BS2 -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 10, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 07, 2020	Variant summary: SCN5A c.6016C>G (p.Pro2006Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0011 in 229592control chromosomes (gnomAD and publication data), including 1 homozygote. The observed variant frequency is approximately 54-fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Long QT Syndrome phenotype (2.1e-05), strongly suggesting that the variant is benign. The variant, c.6016C>G, has been reported in the literature in individuals affected with Long QT Syndrome and sudden death, but was also detected in controls (Aziz_2013, Christiansen_2014, Kapa_2009, Krahn_2009, Marcondes_2017). This variant has been reported not associate with any ECG characteristics in one large cohort, but associate with cardiac arrest and VF in another large cohort (Paludan-Muller_2019). These reports do not provide unequivocal conclusions about association of the variant with Long QT Syndrome. Functional studies have shown the Pro2006Ala variant to exhibit increased persistent sodium currents in whole-cell voltage clamp measurements (Wang_2007, Shinlapawittayatorn_2011). Interestingly, when two variants, P2006A and a common polymorphism H558R, were expressed on the same allele, the cells displayed currents that behaved like wild type (Shinlapawittayatorn_2011). Therefore the biological significance of these in vitro studies is unclear. In fact, a case-control study showed that individuals with the variant of interest did not have significantly different QTc interval times compared to non-variant carriers (Ghouse_2015). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (benign/likely benign n=9, VUS n=3). Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 01, 2015	p.Pro2006Ala in exon 28 of SCN5A: This variant is not expected to have clinical significance because it has been identified in 0.2% (124/63230) of European chr omosomes and 0.23% (15/6614) of Finnish chromosomes by the Exome Aggregation Con sortium (ExAC, http://exac.broadinstitute.org; dbSNP rs45489199). Additionally, proline (Pro) at position 2006 is not conserved in mammals or evolutionarily dis tant species and this variant has been identified in at least 5 mammals. Please note, this variant has been reported in the literature in 4 individuals with lon g QT, 5 individuals with VF, 2 cases of SIDS (Priori 2000, Ackerman 2004, Arnest ad 2007, Krahn 2009, Skinner 2011, Shinlapawittayatorn 2011, Novotny 2011). Stud ies have shown that the p.Pro2006Ala variant exhibits increased persistent sodiu m currents in whole-cell voltage clamp measurements (Wang 2007, Shinlapawittayat orn 2011), but behaves like wild type when expressed with the p.His558Arg varian t (Shinlapawittayatorn 2011). However, these in vitro assays may not accurately represent biological function. -

Brugada syndrome 1 Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 23, 2018	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	Nov 27, 2017	- -

Ventricular fibrillation, paroxysmal familial, type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 23, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Long QT syndrome 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 23, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Dilated cardiomyopathy 1E Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 23, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Sep 02, 2021

- -

SCN5A-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 08, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Sick sinus syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 23, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Progressive familial heart block, type 1A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 23, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2018

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. -

Cardiac arrhythmia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Apr 28, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	2.0
DANN	Benign	0.35
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.11	N
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.011	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.36	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.0	N;N;N;N;N;N;N;N;N
REVEL	Benign	0.28
Sift	Benign	0.60	T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.80	T;T;T;T;T;T;T;T;T
Polyphen		0.0	B;B;.;B;.;B;B;.;.
Vest4		0.13
MVP		0.69
MPC		0.50
ClinPred		0.0037	T
GERP RS		-2.6
Varity_R		0.039
gMVP		0.43

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: rs45489199; hg19: chr3-38591847;