rs12720452

Variant names:

• chr3-38603758-C-T
• rs12720452
• NM_001099404.2:c.1844G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4 BS1_Supporting

The NM_000335.5(SCN5A):​c.1844G>A​(p.Gly615Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00053 in 1,537,994 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).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00056 (0 hom.)
• Consequence: SCN5A NM_000335.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:13 B:1 O:1
• Conservation: PhyloP100: 0.210

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 in the SCN5A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 99 curated pathogenic missense variants (we use a threshold of 10). The gene has 60 curated benign missense variants. Gene score misZ: 2.7504 (below the threshold of 3.09). Trascript score misZ: 4.8279 (above the threshold of 3.09). GenCC associations: The gene is linked to 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=0.36050773).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000558 (773/1385874) while in subpopulation NFE AF= 0.000689 (739/1072578). AF 95% confidence interval is 0.000648. There are 0 homozygotes in gnomad4_exome. There are 362 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.1844G>A	p.Gly615Glu	missense_variant	Exon 12 of 28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.1844G>A	p.Gly615Glu	missense_variant	Exon 12 of 28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.1844G>A	p.Gly615Glu	missense_variant	Exon 12 of 28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.1844G>A	p.Gly615Glu	missense_variant	Exon 12 of 28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes AF: 0.000276 AC: 42 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.000529

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000286 AC: 56 AN: 196144 Hom.: 0 AF XY: 0.000299 AC XY: 31 AN XY: 103844

Gnomad AFR exome AF: 0.000134

Gnomad AMR exome AF: 0.000114

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000563

Gnomad FIN exome AF: 0.0000556

Gnomad NFE exome AF: 0.000518

Gnomad OTH exome AF: 0.000219

GnomAD4 exome AF: 0.000558 AC: 773 AN: 1385874 Hom.: 0 Cov.: 30 AF XY: 0.000533 AC XY: 362 AN XY: 679522

Gnomad4 AFR exome AF: 0.0000956

Gnomad4 AMR exome AF: 0.0000842

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000397

Gnomad4 NFE exome AF: 0.000689

Gnomad4 OTH exome AF: 0.000456

GnomAD4 genome AF: 0.000276 AC: 42 AN: 152120 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74314

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000529

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000432 Hom.: 1

Bravo AF: 0.000264

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000595 AC: 5

ExAC AF: 0.000207 AC: 25

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:13 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:6

-

Clinical Genetics, Academic Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 12, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 29, 2025

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 glutamic acid, which is acidic and polar, at codon 615 of the SCN5A protein (p.Gly615Glu). This variant is present in population databases (rs12720452, gnomAD 0.05%). This missense change has been observed in individual(s) with clinical features of SCN5A-related conditions (PMID: 11997281, 15840476, 19716085, 20129283, 23631430, 24613995, 30079003, 32516855, 32553227). ClinVar contains an entry for this variant (Variation ID: 67691). 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 tolerated. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SCN5A function (PMID: 11997281, 24613995, 31262209). 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. -

Aug 13, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in association with LQTS, CPVT, and as part of postmortem genetic testing for unexplained deaths (PMID: 19716085, 31737537, 32553227, 18071069, 27435932, 27930701, 29874177); Reported in patients with Brugada syndrome; however, at least one individual also harbored a second variant in the SCN5A gene that was deemed deleterious (PMID: 25650408, 20129283, 30193851); Identified in several individuals who developed torsades de pointe after exposure to a QT-prolonging drug (PMID: 11997281, 22584458); Identified in a patient with neonatal onset DCM who also harbored an additional variant in the VCL gene; family studies identified the p.(G615E) variant in the proband's unaffected mother who was negative for the VCL variant, as well as in three siblings with no symptoms but reported to have a prolonged QT interval (PMID: 32516855); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24055113, 19841300, 34461752, 22378279, 23414114, 25637381, 24713084, 23631430, 24613995, 15840476, 14760488, 19862833, 23861362, 27930701, 27435932, 22584458, 27153395, 26746457, 28412158, 29874177, 29728395, 28798025, 31262209, 30193851, 31737537, 32553227, 20129283, 19716085, 18071069, 11997281, 25650408, 32516855, 30079003, 30203441) -

Jan 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:2

Feb 11, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Gly615Glu variant in SCN5A has been reported in at least 10 individuals with LQTS, 4 individuals with sudden death, 1 individual with Brugada syndrome, 1 individual with HCM and 1 individual with delayed enhancement in LV (Albert 2008, Beyder 2010, Itoh 2016, Kapplinger 2009, Le Scouarnec 2015, Lieve 2013, Methner 2016, Ng 2013, Paulussen 2004, Sanchez 2016, Tester 2005, Yang 2002). In vitro functional studies provide some evidence that the p.Gly615Glu variant may impact protein function (Beyder 2014, Albert 2008). However, these types of assays may not accurately represent biological function. This variant has also been reported in ClinVar (Variation ID 67691) and has been identified in 50/106156 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs12720452). Computational prediction tools and conservation analysis suggest that the p.Gly615Glu variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, due to conflicting data, the p.Gly615Glu variant is uncertain. ACMG/AMP Criteria applied: PS4, PP3, PS3_S, BS1 (Richards 2015). -

Aug 16, 2021

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.1844G>A (p.Gly615Glu) results in a non-conservative amino acid change located in the Voltage-gated Na+ ion channel, cytoplasmic domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00028 in 199960 control chromosomes. The observed variant frequency is approximately 13 fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Long QT Syndrome With Sudden Cardiac Death phenotype (2.1e-05), strongly suggesting that the variant is benign. c.1844G>A has been reported in the literature in multiple LQTS patients, including some diagnosed with Sudden Cardiac Death and LQTS triggered by quinidine (e.g. Lieve_2013, Sanchez_2016, Methner_2016, Anderson_2017, Marschall_2019). In addition, this variant was also reported in one proband with neonatal DCM, one family member with episode of chest pain with normal QT interval, and three aymptomatic family members with prolonged QT interval (Hawley_2020). These data do not provide unequivocal conclusions about association of the variant with LQTS or other diseases. Functional studies have reported conflicting results with no effect on the peak amplitude of voltage-gated sodium current (Yang_2002), positive shifts in voltage dependence of activation, with altered activation kinetics and slower activation than wildtype associated with this variant (Beyder_2014), and disruptions in mechanosensitivity (Strege_2019). Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Pathogenic n=2, VUS n=8). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Long QT syndrome 3 Uncertain:2

Feb 02, 2022

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_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0103 - Loss of function and gain of function are both known mechanisms of disease in this gene. Loss of function is usually associated with Brugada syndrome 1 (MIM#601144) and sick sinus syndrome 1 (SSS) (MIM#608567), whereas gain of function is usually associated with long QT syndrome-3 (LQTS) (MIM#603830). Dilated cardiomyopathy 1E (DCM) (MIM#601154) can be caused by variants with either a loss or gain of function mechanism (PMID: 29798782). However, some variants simultaneously result in both a loss and gain of function effect, and have been observed in patients with LQTS, Brugada or SSS, and patients with a blended phenotype. Additionally, different studies have shown conflicting mechanisms in association with familial atrial fibrillation 10 (MIM#614022) (PMIDs: 29806494, 19167345, 26798387, 29798782). (I) 0108 - This gene is associated with both recessive and dominant disease. Most conditions associated with this gene are dominantly inherited, however SSS is caused by biallelic variants (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to glutamic acid. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2) (66 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated DI-DII intracellular linker region (PMID: 19841300). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported multiple times as a VUS in ClinVar but also as pathogenic. This variant has been reported in individuals affected with LQTS, sudden cardiac death, IBS and DCM but was also present in control samples (PMID: 11997281, PMID: 18071069, PMID: 19841300, PMID: 24613995, PMID: 25904541, PMID: 32516855). (I) 1010 - Functional evidence for this variant is inconclusive. Functional studies on this variant have reported differing results, from no effect on the peak amplitude of voltage-gated sodium current (PMID: 11997281) to positive shifts in voltage dependence of activation, with altered activation kinetics and slower activation (PMID: 24613995) and also possible mechanosensitivity effects (PMID: 31262209). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Apr 06, 2017

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Long QT syndrome, drug-associated Uncertain:1 Benign:1

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Death in infancy Pathogenic:1

Mar 27, 2015

Forensic Genetics Laboratory, Harris County Institute of Forensic Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Death in early adulthood Pathogenic:1

Mar 28, 2015

Forensic Genetics Laboratory, Harris County Institute of Forensic Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiovascular phenotype Uncertain:1

Aug 25, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G615E variant (also known as c.1844G>A), located in coding exon 11 of the SCN5A gene, results from a G to A substitution at nucleotide position 1844. The glycine at codon 615 is replaced by glutamic acid, an amino acid with similar properties. This alteration has been reported in subjects with acquired long QT syndrome, long QT syndrome, Brugada syndrome, and dilated cardiomyopathy; however, in some cases, clinical details were limited and/or additional cardiac variants were detected (Yang P et al. Circulation, 2002 Apr;105:1943-8; Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303; Lieve KV et al. Genet Test Mol Biomarkers, 2013 Jul;17:553-61; Le Scouarnec S et al. Hum. Mol. Genet., 2015 May;24:2757-63; Hawley MH et al. Hum Mutat, 2020 09;41:1577-1587). It has also been reported in sudden death and stillbirth cohorts (Albert CM et al. Circulation, 2008 Jan;117:16-23; Methner DN et al. Genome Res., 2016 Sep;26:1170-7; Munroe PB et al. Circ Genom Precis Med, 2018 01;11:e001817). This variant has also been seen in exome cohorts, as well as an irritable bowel syndrome cohort (Dorschner MO et al. Am J Hum Genet. 2013;93(4):631-40; Beyder A et al. Gastroenterology, 2014 Jun;146:1659-68; Amendola LM et al. Genome Res. 2015;25(3):305-15; Maxwell KN et al. Am. J. Hum. Genet., 2016 May;98:801-17). Functional studies have shown little or no impact on voltage function, but possible mechanosensitivity effects; however, the clinical relevance of these findings is uncertain (Yang P et al. Circulation, 2002 Apr;105:1943-8; Albert CM et al. Circulation, 2008 Jan;117:16-23; Strege PR et al. Channels (Austin), 2019 12;13:287-298). Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). 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 conflicting at this time, the clinical significance of this alteration remains unclear. -

Cardiac arrhythmia Uncertain:1

Dec 21, 2022

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 glutamic acid at codon 615 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). Functional studies have shown that this variant may alter sodium channel activation and inactivation kinetics (PMID: 18071069, 24613995) Additionally, one functional study has shown that the mutant channel affects mechanosensitivity of voltage-dependent gating compared to the wild type channel (PMID: 31262209). This variant has been reported in individuals affected with Brugada syndrome (PMID: 20129283), irritable bowel syndrome (PMID: 24613995) and sudden cardiac death (PMID: 18071069). This variant has been reported in an individual affected with long QT syndrome, who also carried a pathogenic variant in the KCNQ1 gene (PMID: 23631430) and in an individual affected with catecholaminergic polymorphic ventricular tachycardia (PMID: 32553227). This variant has also been reported in one individual affected with neonatal dilated cardiomyopathy and three individuals with prolonged QT intervals in one family (PMID: 32516855). This variant has been identified in 66/227496 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. -

Congenital long QT syndrome Other:1

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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:14760488;PMID:15840476;PMID:19716085;PMID:19841300). 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	0.12
CardioboostCm	Benign	0.0037
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Uncertain	0.070
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	.;.;.;.;.;D;.;.;.
Eigen	Benign	-0.035
Eigen_PC	Benign	-0.074
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.77	.;T;T;T;T;T;T;.;T
M_CAP	Pathogenic	0.42	D
MetaRNN	Benign	0.36	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Uncertain	2.3	.;M;.;.;.;M;.;.;.
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-2.1	N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.63
Sift	Benign	0.091	T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.66	T;T;T;T;T;T;T;T;T
Polyphen		0.85	P;D;.;P;.;D;D;.;.
Vest4		0.53
MVP		0.84
MPC		1.2
ClinPred		0.046	T
GERP RS		4.2
Varity_R		0.12
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs12720452; hg19: chr3-38645249;