rs749697698

Variant names:

• chr3-38551519-GAGA-G
• rs749697698
• NM_001099404.2:c.4850_4852delTCT

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM4_Supporting PP5_Very_Strong

The NM_001099404.2(SCN5A):​c.4850_4852delTCT​(p.Phe1617del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000246 in 1,461,624 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: SCN5A NM_001099404.2 disruptive_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:19
• Conservation: PhyloP100: 9.31
• Publications: 16 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: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 17 uncertain in NM_001099404.2
• PM4: Nonframeshift variant in NON repetitive region in NM_001099404.2. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 3-38551519-GAGA-G is Pathogenic according to our data. Variant chr3-38551519-GAGA-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 201572.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.4850_4852delTCT	p.Phe1617del	disruptive_inframe_deletion	Exon 28 of 28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.4847_4849delTCT	p.Phe1616del	disruptive_inframe_deletion	Exon 28 of 28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.4850_4852delTCT	p.Phe1617del	disruptive_inframe_deletion	Exon 28 of 28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.4847_4849delTCT	p.Phe1616del	disruptive_inframe_deletion	Exon 28 of 28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 250930 AF XY: 0.0000295

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000246 AC: 36 AN: 1461624 Hom.: 0 AF XY: 0.0000275 AC XY: 20 AN XY: 727088

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000252 AC: 28 AN: 1111838

Other (OTH) AF: 0.0000331 AC: 2 AN: 60366

GnomAD4 genome Cov.: 28

Alfa AF: 0.0000434 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:19

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Jul 25, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in multiple individuals in association with LQTS, Brugada syndrome, and sick sinus syndrome (SSS) (PMID: 10973849, 14523039, 17081365, 19716085, 19017345, 20877689, 22840528, 25236808, 26669661, 32161207); Identified in 45 individuals from a large Dutch-German founder population, including one homozygous individual, and found that this variant segregated with divergent and overlapping cardiac phenotypes including LQTS, cardiac conduction disease (CCD), BrS, and isorhythmic dissociation (PMID: 28782696); Not observed at significant frequency in large population cohorts (gnomAD); In-frame deletion of one amino acid in a non-repeat region; Published functional studies demonstrated that this variant alters sodium current kinetics and may cause both gain-of-function and loss-of-function effects on sodium currents, depending on the membrane potential (PMID: 14523039, 15665061, 20539757); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 14523039, 20539757, 15665061, 17081365, 19017345, 20877689, 22840528, 25236808, 26669661, 20448214, 19716085, 24578642, 29017927, 30364184, 31582838, 32454217, 31737537, 32780330, 34426522, 33221895, 32161207, 33673806, 10973849, 28782696, 37547970) -

Sep 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.4850_4852del, results in the deletion of 1 amino acid(s) of the SCN5A protein (p.Phe1617del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs749697698, gnomAD 0.003%). This variant has been observed in individuals with German-Dutch descent and long QT syndrome and sick sinus syndrome and long-QT syndrome and conduction disease and Brugada syndrome (PMID: 10973849, 14523039, 17081365, 19716085, 22840528, 28782696). It is commonly reported in individuals of Dutch ancestry (PMID: 10973849, 14523039, 17081365, 19716085, 22840528, 28782696). ClinVar contains an entry for this variant (Variation ID: 201572). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects SCN5A function (PMID: 15665061, 20448214). For these reasons, this variant has been classified as Pathogenic. -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 13, 2021

Johns Hopkins Genomics, Johns Hopkins University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant (rs749697698) is rare in a large population database (5/250930 total alleles, 0.002%, no homozygotes) and has an entry in ClinVar. This variant has been reported in families and/or individuals with autosomal dominant long QT syndrome-3 or Brugada syndrome-1. This variant causes a deletion of a single phenylalanine residue in the SCNA5 protein, which is located in the short extracellular loop between segments S3 and S4 in the repeat domain IV. Functional studies using cultured mammalian cells have demonstrated that this variant alters sodium current kinetics and may cause either an increase or decrease in sodium currents, depending on the membrane potential. We consider this variant to be pathogenic. -

Oct 14, 2019

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PP1_Strong PM4 -

Jul 13, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Long QT syndrome 3 Pathogenic:3

Oct 14, 2021

Clinical Genetics Laboratory, University Hospital Schleswig-Holstein

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 29, 2016

Center for Medical Genetics Ghent, University of Ghent

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been identified in large population databases (Gnomad, 1000 Genomes, Go NL, Exome Variant Server). In addition, the variant has been reported previously in individuals with longQT syndrome. The variant results in an inframe deletion of one amino acid and thus reduces the length of the protein. Functional studies demonstrated that this variant alters sodium current kinetics (PMID: 14523039; PMID: 15665061). -

Feb 01, 2018

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Brugada syndrome 1 Pathogenic:2

May 17, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PS4,PS3_MOD,PM4,PM2_SUP -

Jul 24, 2025

Institute of Human Genetics Munich, TUM University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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 Pathogenic:2

Feb 24, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PM4+PS3_Moderate+PS4_Moderate+PM3 -

Cardiac arrhythmia Pathogenic:2

Oct 07, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes a deletion of phenylalanine at codon 1617 of the SCN5A protein. This variant is also known as Phe1616del in the literature based on a different NM_000335 transcript. This variant is found within a highly conserved region of the transmembrane domain DIV. Rare nontruncating variants in this region (a.a. 1530-1771) have been shown to be significantly overrepresented in individuals with long QT syndrome or Brugada syndrome (PMID: 32893267). Functional studies have shown this variant to cause alteration in sodium current kinetics and cause both gain-of-function and loss-of-function effects on sodium currents, depending on the membrane potential (PMID: 14523039, 15665061, 20448214). This variant has been reported in 45 individuals of Dutch and German descents in a 16-generation pedigree and has been shown to highly associate and segregate with long QT syndrome (PMID: 28782696). Some carriers in this population also exhibited other overlapping cardiac phenotypes including cardiac conduction defect, Brugada syndrome and/or isorhythmic atrioventricular dissociation. This variant has been observed in additional unrelated individuals affected with long QT syndrome (PMID: 10973849, 32454217, 36764349), several individuals with Brugada syndrome (PMID: 20877689, 22840528, 32893267, 33221895, 36516610), one individual with congenital sick sinus syndrome (PMID: 14523039), and one individual with sudden explained death (PMID: 34620408). This variant has been identified in 5/250930 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Aug 01, 2022

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SCN5A c.4850_4852delTCT (p.Phe1617del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 2e-05 in 255580 control chromosomes (gnomAD). c.4850_4852delTCT has been reported in the literature in multiple individuals affected LQTS (examples: Splawski_2000, Kapplinger_2009, Goldenberg_2011), Sick Sinus syndrome (example: Benson_2003) and Brugada syndrome (examples: Liang_2010 and Crotti_2012). These data indicate that the variant is very likely to be associated with disease. Multiple functional studies demonstrated that this variant alters sodium current kinetics and may cause either an increase or decrease in sodium currents (examples: Benson_2003, Chen_2005, Butters_2010 and Gui_2010). Eleven submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=5) and likely pathogenic (n=6). Based on the evidence outlined above, the variant was classified as pathogenic. -

Sick sinus syndrome 1 Pathogenic:1

Feb 14, 2022

DASA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 201572; PMID: 28782696; 25236808) - PS4. The variant is present at low allele frequencies population databases (rs749697698 - gnomAD 0.0001993%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. Protein length variants as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants - PM4. The variant co-segregated with disease in multiple affected family members (PMID: 28782696; 25236808) - PP1_strong. In summary, the currently available evidence indicates that the variant is pathogenic. -

Congenital long QT syndrome Pathogenic:1

Aug 30, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes a deletion of phenylalanine at codon 1617 of the SCN5A protein. This variant is also known as Phe1616del in the literature based on a different NM_000335 transcript. This variant is found within a highly conserved region of the transmembrane domain DIV. Rare nontruncating variants in this region (a.a. 1530-1771) have been shown to be significantly overrepresented in individuals with long QT syndrome or Brugada syndrome (PMID: 32893267). Functional studies have shown this variant to cause alteration in sodium current kinetics and may cause both gain-of-function and loss-of-function effects on sodium currents, depending on the membrane potential (PMID: 14523039, 15665061, 20448214). This variant has been reported in 45 individuals of the Netherlands and Germany descents in a 16-generation pedigree and has been shown to highly associate and segregate with long QT syndrome (PMID: 28782696). Some carriers in this founder population also exhibited other overlapping cardiac phenotypes including cardiac conduction defect, Brugada syndrome and/or isorhythmic atrioventricular dissociation. This variant has been observed in additional unrelated individuals affected with long QT syndrome (PMID: 10973849, 32454217, 36764349), several individuals with Brugada syndrome (PMID: 20877689, 22840528, 32893267, 33221895, 36516610), one individual with congenital sick sinus syndrome (PMID: 14523039), and one individual with sudden explained death (PMID: 34620408). This variant has been identified in 5/250930 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Long QT syndrome Pathogenic:1

May 11, 2015

Blueprint Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Pathogenic:1

Jan 24, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4850_4852delTCT (p.F1617del) alteration, located in coding exon 27 of the SCN5A gene, results from an in-frame TCT deletion at nucleotide positions 4850 and 4852. This results in the deletion of a phenylalanine residue at codon 1617. Based on data from gnomAD, this variant has an overall frequency of 0.002% (5/250930) total alleles studied. The highest observed frequency was 0.003% (1/30614) of South Asian alleles. This variant has been detected in individuals reported to have, or referred for genetic testing for, long QT syndrome (LQTS) and Brugada syndrome (BrS) (Splawski, 2000; Kapplinger, 2009; Liang, 2010; Crotti, 2012). One study of a Dutch-German population reported this alteration as a founder mutation that was significantly associated with the risk of long QT syndrome (Ter Bekke, 2017). This amino acid position is not well conserved in available vertebrate species. Functional studies have suggested this variant alters sodium channel kinetics; however, the physiological relevance of the observed impact is unclear (Benson, 2003; Chen, 2005; Gui, 2010). This alteration is predicted to be deleterious by in silico analysis (Choi, 2012). Based on the available evidence, this alteration is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.3
Mutation Taster		=4/96	disease causing

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: rs749697698; hg19: chr3-38593010; COSMIC: COSV61136454; COSMIC: COSV61136454;