rs749697698

chr3-38551519-GAGA-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PM4_Supporting PP3 PP5_Very_Strong

The NM_001099404.2(SCN5A):c.4850_4852del(p.Phe1617del) variant causes a 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 inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 9.31

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 14 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_001099404.2
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001099404.2. Strenght limited to Supporting due to length of the change: 1aa.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 3-38551519-GAGA-G is Pathogenic according to our data. Variant chr3-38551519-GAGA-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 201572.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38551519-GAGA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_000335.5	c.4847_4849del	p.Phe1616del	inframe_deletion	28/28	ENST00000423572.7
SCN5A	NM_001099404.2	c.4850_4852del	p.Phe1617del	inframe_deletion	28/28	ENST00000413689.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.4850_4852del	p.Phe1617del	inframe_deletion	28/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.4847_4849del	p.Phe1616del	inframe_deletion	28/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 250930 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135676

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 SAS exome AF: 0.0000327

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000252

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 28

Alfa AF: 0.0000434 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 13, 2023	Reported in multiple individuals in association with LQTS, Brugada syndrome, and sick sinus syndrome (SSS) (Splawski et al., 2000; Benson et al., 2003; Liang et al., 2006; Kapplinger et al., 2009, Zellerhoff et al., 2009; Liang et al., 2010; Crotti et al., 2012; Tan et al., 2014; Itoh et al., 2016; Fukuyama et al., 2020); 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 (Ter Bekke et al., 2017); 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 (Benson et al., 2003; Chen et al., 2005; Gui et al., 2010); Not observed at significant frequency in large population cohorts (gnomAD); In-frame deletion of one amino acid in a non-repeat region; 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, 28782696, 19716085, 24578642, 29017927, 30364184, 31582838, 32454217, 31737537, 32780330, 34426522, 33221895, 10973849, 32161207, 33673806) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 28, 2023	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 protein 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	May 13, 2021	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 14, 2019	PS3, PP1_Strong PM4 -

Long QT syndrome 3 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	Feb 01, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Jun 29, 2016	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). -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	Oct 14, 2021	- -

Cardiac arrhythmia Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 01, 2022	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 13, 2023	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 that this variant causes a reduced peak sodium current density and also an increased sodium current at positive command potentials (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 another two unrelated individuals affected with long QT syndrome (PMID: 10973849, 32454217), one individual affected with congenital sick sinus syndrome (PMID: 14523039), one with sudden explained death (PMID: 34620408), and several individuals with or suspected with Brugada syndrome (PMID: 20877689, 22840528, 32893267, 33221895, 36516610). 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. -

Brugada syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

May 17, 2023

Criteria applied: PS4,PS3_MOD,PM4,PM2_SUP -

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:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 24, 2022

- -

Sick sinus syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

DASA

Feb 14, 2022

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. -

Long QT syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

May 11, 2015

- -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 14, 2023

The c.4850_4852delTCT variant (also known as p.F1617del) is located in coding exon 27 of the SCN5A gene. This variant results from an in-frame TCT deletion at nucleotide positions 4850 to 4852. This results in the in-frame deletion of a phenylalanine residue at codon 1617, located in the extracellular loop that links the S3 and S4 transmembrane-spanning helices of the DIV domain. 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 I et al. Circulation. 2000;102(10):1178-85; Kapplinger JD et al. Heart Rhythm. 2009;6(9):1297-303; Liang P et al. J Cardiovasc Dis Res. 2010;1(2):69-74; Crotti L et al. J Am Coll Cardiol. 2012;60(15):1410-8). This variant has also been reported to co-occur with other variants in arrhythmia-related genes, including a case of pediatric onset sick sinus syndrome, and severe LQTS where relatives with only this alteration were unaffected or less severely affected (Benson DW et al. J Clin Invest. 2003;112(7):1019-28; Tan VH et al. Heart Lung. 2014;43(6):541-5). 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 RMA et al. Heart Rhythm. 2017 12;14(12):1873-1881). Functional studies have suggested this variant alters sodium channel kinetics; however, the physiological relevance of the observed impact is unclear (Benson DW et al. J Clin Invest. 2003;112(7):1019-28; Chen T et al. Am J Physiol Heart Circ Physiol. 2005;288(6):H2666-76; Gui J. PLoS ONE. 2010;5(6):e10985). This amino acid position is highly conserved through mammals but not in all available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

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: rs749697698; hg19: chr3-38593010;