rs199473603

chr3-38562467-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP2 PP3_Strong PP5_Strong

The NM_001099404.2(SCN5A):c.3911C>T(p.Thr1304Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000343 in 1,613,484 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/23 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T1304T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00036 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:4 U:14 O:1
• Conservation: PhyloP100: 10.0

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 Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SCN5A
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.939
• PP5: Variant 3-38562467-G-A is Pathogenic according to our data. Variant chr3-38562467-G-A is described in ClinVar as [Uncertain_significance]. Clinvar id is 67835.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=13, not_provided=1, Likely_pathogenic=3, Pathogenic=1}. Variant chr3-38562467-G-A is described in Lovd as [Pathogenic]. Variant chr3-38562467-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.3911C>T	p.Thr1304Met	missense_variant	22/28	ENST00000413689.6
SCN5A	NM_000335.5	c.3908C>T	p.Thr1303Met	missense_variant	22/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.3911C>T	p.Thr1304Met	missense_variant	22/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.3908C>T	p.Thr1303Met	missense_variant	22/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000178 AC: 44 AN: 247644 Hom.: 0 AF XY: 0.000208 AC XY: 28 AN XY: 134368

Gnomad AFR exome AF: 0.000130

Gnomad AMR exome AF: 0.0000873

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000330

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000338

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000357 AC: 521 AN: 1461146 Hom.: 0 Cov.: 31 AF XY: 0.000341 AC XY: 248 AN XY: 726770

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000896

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000814

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000429

Gnomad4 OTH exome AF: 0.000414

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152338 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74480

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000367

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000436 Hom.: 0

Bravo AF: 0.000261

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000239 AC: 1

ESP6500EA AF: 0.000472 AC: 4

ExAC AF: 0.000207 AC: 25

EpiCase AF: 0.000491

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:4 Uncertain:14 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 16, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1304 of the SCN5A protein (p.Thr1304Met). This variant is present in population databases (rs199473603, gnomAD 0.03%). This missense change has been observed in individual(s) with SCN5A-related conditions (PMID: 10508990, 17210839, 17210841, 19716085, 19841300, 24631775, 25210526, 28341588, 30847666). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 67835). 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. Experimental studies have shown that this missense change affects SCN5A function (PMID: 17210841). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 18, 2020	The SCN5A c.3911C>T; p.Thr1304Met variant (rs199473603) is reported in the literature in individuals affected with long QT syndrome (Kapa 2009, Wattanasirichaigoon 1999) or Brugada syndrome (Kim 2014), which have different mechanisms of pathogenicity. This variant is also reported with conflicting interpretations by multiple laboratories in ClinVar (Variation ID: 67835), and is found in the non-Finnish European population with an allele frequency of 0.031% (40/127748 alleles) in the Genome Aggregation Database. The threonine at codon 1304 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, functional analyses of the variant protein show conflicting effects on channel function (Beyder 2014, Wang 2007). Due to conflicting information, the clinical significance of the p.Thr1304Met variant is uncertain at this time. References: Beyder A et al. Loss-of-function of the voltage-gated sodium channel NaV1.5 (channelopathies) in patients with irritable bowel syndrome. Gastroenterology. 2014 Jun;146(7):1659-1668. Kapa S et al. Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants. Circulation. 2009 Nov 3;120(18):1752-60. Kim G et al. A pediatric case of Brugada syndrome diagnosed by fever-provoked ventricular tachycardia. Korean J Pediatr. 2014 Aug;57(8):374-8. Wang DW et al. Cardiac sodium channel dysfunction in sudden infant death syndrome. Circulation. 2007 Jan 23;115(3):368-76. Wattanasirichaigoon D et al. Sodium channel abnormalities are infrequent in patients with long QT syndrome: identification of two novel SCN5A mutations. Am J Med Genet. 1999 Oct 29;86(5):470-6. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 24, 2023	Reported in individuals with various cardiac phenotypes, including LQTS, Brugada syndrome, lone atrial fibrillation, sudden infant death syndrome, cardiomyopathy, and T-wave inversion (PMID: 17210839, 10508990, 10973849, 19716085, 22685113, 25210526, 23465283, 29764897, 31514951, 34065239); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Functional studies have been reported and show conflicting results (PMID: 17210841, 24613995); This variant is associated with the following publications: (PMID: 10973849, 19716085, 28316956, 31514951, 30193851, 22685113, 23465283, 22378279, 25637381, 25210526, 10961955, 18503232, 23272275, 24055113, 24613995, 25351510, 25410959, 25904541, 25898860, 27153395, 29247119, 28412158, 28341588, 30677491, 28988457, 31019283, 31043699, 32048431, 30291343, 30847666, 29764897, 26743238, 19841300, 24144883, 24631775, 26746457, 31395126, 34426522, 34065239, 34621001, 34461752, 33772059, 35060774, 30203441, 10508990, 17210839, 29790872, 17210841) -
Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Mar 31, 2017	- -

Long QT syndrome 3 Pathogenic:2 Uncertain:1

Likely pathogenic, flagged submission	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Nov 21, 2018	- -
Uncertain significance, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Jan 04, 2024	- -
Pathogenic, flagged submission	research	Donald Williams Parsons Laboratory, Baylor College of Medicine	Sep 13, 2013	This variant has been previously reported as disease-causing. It was an incidental finding in our study, maternally inherited in a 8-year-old male with medulloblastoma. -

Brugada syndrome 1 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	May 14, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 20, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Brugada syndrome Pathogenic:1

Likely pathogenic, flagged submission

clinical testing

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Jan 13, 2017

- -

Long QT syndrome Pathogenic:1

Likely pathogenic, flagged submission

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 26, 2018

The p.Thr1304Met variant in SCN5A has been reported in 3 individuals with long Q T syndrome, 1 infant with sudden infant death syndrome, 1 individual with Brugad a syndrome, 1 individual with early-onset atrial fibrillation (Wattanasirichaigo on 1999, Priori 2000, Splawski 2000, Arnestad 2007, Olesen 2012, Kim 2014). This variant segregated with LQTS in 2 affected relatives from 1 family and with Br ugada syndrome in 1 affected relative from 1 family. However, other clinical lab oratories have observed this variant in individuals who carried other disease-ca using variants (GeneDx, Emory, Invitae; personal communication) and this variant has been reported in multiple healthy individuals (Weeke 2015, Kapplinger 2015) . Additionally, it is unclear if the same variant would be causative for such a diverse set of phenotypes, suggesting that it may not have a functional effect. This variant has also been identified in 0.03% (35/126116) of European chromosom es by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs199473603). Additionally, in vitro functional studies have shown confli cting results (Want 2007, Makita 2008, Beyder 2014). In summary, due to the pres ence of conflicting data, the clinical significance of the p.Thr1304Met variant is uncertain. ACMG/AMP Criteria applied: PP1; BP5. -

SCN5A-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 12, 2024

The SCN5A c.3911C>T variant is predicted to result in the amino acid substitution p.Thr1304Met. This variant was reported in individuals with long QT syndrome and Brugada syndrome (Wattanasirichaigoon et al. 1999. PMID: 10508990; Arnestad et al. 2007. PMID: 17210839; Kapplinger et al. 2009. PMID: 19716085; Kapa et al. 2009. PMID: 19841300; Table SVI, Milman et al. 2021. PubMed ID: 34461752). Functional studies showed conflicting evidences of pathogenicity for this variant. Although one study suggested this variant significantly increased persistent sodium currents and faster recovery from inactivation (Wang et al. 2007. PMID: 17210841), another demonstrated no difference from wild type SCN5A (Beyder et al. 2014. PubMed ID: 24613995). This variant also had conflicting interpretations of pathogenicity in the literature ranging from benign to pathogenic (Table S1, Amendola et al. 2015. PMID: 25637381; Table S1, Paludan-Müller et al. 2019. PubMed ID: 31043699; Table SVI, Milman et al. 2021. PubMed ID: 34461752). This variant is reported in 0.031% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations of benign, uncertain significance, likely pathogenic, and pathogenic in ClinVar (www.ncbi.nlm.nih.gov/clinvar/variation/67835/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Conduction disorder of the heart Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Robert's Program, Boston Children's Hospital

Jan 17, 2020

This variant is classified as a Variant of Uncertain Significance based on the following ACMG/AMP criteria: BS2, PP3, and PS3. Published functional in vitro and in vivio evidence (Wang et al 2007, Anderson et al 2017) supports this variant having an effect on the SCN5A protein, but population frequency (MAF of 0.0003 in non-finnish Europeans) is high compared to frequency of disease. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 04, 2024

The c.3911C>T (p.T1304M) alteration is located in exon 22 (coding exon 21) of the SCN5A gene. This alteration results from a C to T substitution at nucleotide position 3911, causing the threonine (T) at amino acid position 1304 to be replaced by a methionine (M). Based on data from gnomAD, the T allele has an overall frequency of 0.017% (46/279030) total alleles studied. The highest observed frequency was 0.031% (40/127748) of European (non-Finnish) alleles. This alteration has been reported in association with long QT syndrome (Wattanasirichaigoon, 1999; Kapplinger, 2009). In one family, alteration carriers showed variable clinical and electrophysiological phenotypes with several having borderline findings (Wattanasirichaigoon, 1999). This alteration was also detected in individuals with a transient Brugada pattern, lone atrial fibrillation, or sudden infant death syndrome (Wang, 2007; Olesen, 2012; Wang, 2014; Kim, 2014). In addition, this alteration was reported in hypertrophic cardiomyopathy, dilated cardiomyopathy cohorts as well as exome sequencing and cohorts not selected for the presence of cardiovascular disease; however, limited clinical information was provided (Andreasen, 2013; Dorschner, 2013; Lopes, 2015; Amendola, 2015; Van Driest, 2016; Gigli, 2019; Diebold, 2020). This amino acid position is highly conserved in available vertebrate species. While some research groups reported that this alteration would lead to gain of function effects (Wang, 2007; Arnestad, 2007), others found no significant difference between mutant and wild type channel function (Makita, 2008; Beyder, 2014); however, the experimental systems were not the same and the physiological significance of these results is unclear. This alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Cardiac arrhythmia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Dec 04, 2023

This missense variant replaces threonine with methionine at codon 1304 of the SCN5A protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. Functional studies have shown inconsistent results regarding the impact of this variant on the SCN5A ion channel function (PMID: 17210841, 18451998). This variant has been reported in individuals affected with long QT syndrome (PMID: 19841300), early-onset lone atrial fibrillation (PMID: 22685113, 24144883), sudden unexplained death (PMID: 17210839, 17210841, 24631775, 32652122), and dilated cardiomyopathy (PMID: 36129056). This variant has been reported to segregate with long QT syndrome in multiple members of a family (PMID: 10508990). This variant has been reported in a small family with Brugada syndrome (PMID: 25210526). This variant has also been identified in 46/279030 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Due to the conflicting functional study results and appreciable allele frequency in the general population, the role of this variant in disease cannot be determined conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Congenital long QT syndrome 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 Long QT syndrome in the following publications (PMID:10508990;PMID:10961955;PMID:17210839;PMID:19716085;PMID:19841300;PMID:17210841;PMID:22378279;PMID:22685113). 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	Pathogenic	0.79
CardioboostArm	Pathogenic	1.0
CardioboostCm	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Pathogenic	29
Dann	Uncertain	1.0
Eigen	Pathogenic	0.79
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.3	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;D;.;D;D;.;.
Vest4		0.95
MVP		0.99
MPC		1.5
ClinPred		0.90	D
GERP RS		4.0
Varity_R		0.83
gMVP		0.97

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: rs199473603; hg19: chr3-38603958; COSMIC: COSV61127198;