rs794728924

Positions:

• chr3-38550904-TCAGA-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001099404.2(SCN5A):​c.5464_5467del​(p.Glu1823HisfsTer10) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,680 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SCN5A NM_001099404.2 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 2.06

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 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 34 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-38550904-TCAGA-T is Pathogenic according to our data. Variant chr3-38550904-TCAGA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 201573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38550904-TCAGA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_000335.5	c.5461_5464del	p.Glu1822HisfsTer10	frameshift_variant	28/28	ENST00000423572.7
SCN5A	NM_001099404.2	c.5464_5467del	p.Glu1823HisfsTer10	frameshift_variant	28/28	ENST00000413689.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.5464_5467del	p.Glu1823HisfsTer10	frameshift_variant	28/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.5461_5464del	p.Glu1822HisfsTer10	frameshift_variant	28/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249656 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135402

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461680 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 727128

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Likely pathogenic, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jul 24, 2017	p.Glu1823Hisfs*10 (c.5464_5467delTCTG) in exon 28 the SCN5A gene (NM_198056.2) Chromosome position 3:38592396 CAGA / - Found in a 4-year-old boy with sick sinus syndrome and an ASD vs PFO, plus a family history of sick sinus syndrome and VSD. Another patient at our center, a 6-year-old boy, has this variant as well, and he has a type 1 Brugada pattern on EKG. Based on the information reviewed below, we classify it as Likely Pathogenic, concluding that there is sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing. This variant has been reported in 2 unrelated individuals: one affected with sick sinus syndrome and monomorphic VT, and another who had genetic testing for Brugada syndrome. Marquez et al., 2007 (PMID: 18361072) from Mexico reported it in an 8 year-old male with congenital sick sinus syndrome—including bradycardia and sinus pauses of up to 3.72 seconds—cardiac conduction disease, and syncopal events due to VT. There was no family history of SCD. His EKGs showed first-degree (and later second-degree) AV block, RBBB with ST segment elevation, prolonged QTc interval (550 msec), and recurrent monomorphic VT (no torsades de pointes). He presented with fetal bradycardia and developed atrial flutter and RBBB during his first year of life. After ablation of the atrial flutter at age 3, sinus node disease was detected with pauses of up to 3.72 seconds. A pacemaker was implanted at age 5 because of sustained, monomorphic VT thought to be bradycardia dependent. A propafenone test designed to unmask Brugada syndrome instead led to severe QRS widening and transient asystole. However, syncopal events attributed to VT continued, by report. Tan et al., 2007 (PMID: 17897635) report that there was incomplete penetrance of the variant in the boy’s family: The variant was present in 6 asymptomatic family members, with only two of them showing mild EKG phenotypes (bradycardia with intraventricular conduction delay, first degree AV block, abnormal repolarization). Tan et al. did in vitro patch clamp studies showing a severe loss of channel function. This missense change reduced channel current density by 90% compared to wildtype. In addition, there were changes in gating kinetics that led to reduced peak and early sodium currents and an increase in late sodium current. This same variant was also reported by the Brugada group in an unrelated individual tested for Brugada syndrome (Kapplinger et al., 2010). This sequence change results in a premature translational stop signal in the SCN5A gene (p.Glu1823Hisfs*10). While this is not anticipated to result in nonsense mediated decay, according to the Invitae report, it is expected to disrupt the last 194 amino acids of the SCN5A protein. Invitae notes that a missense variant downstream of this variant (p.HIs1849Arg) has been determined to be pathogenic (PMID: 26392562), suggesting that deletion of this region of the SCN5A protein is causative of disease. This variant was reported in 1 individual with Latino ancestry in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Our patient’s ancestry is Latino as well. There is good sequencing coverage at this site. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 08, 2024	This sequence change creates a premature translational stop signal (p.Glu1823Hisfs*10) in the SCN5A gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 194 amino acid(s) of the SCN5A protein. This variant is present in population databases (rs794728924, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with sick sinus syndrome and ventricular tachycardia (PMID: 18361072). ClinVar contains an entry for this variant (Variation ID: 201573). 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 premature translational stop signal affects SCN5A function (PMID: 17897635). This variant disrupts the p.His1849 amino acid residue in SCN5A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26392562). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 04, 2022	Reported in one individual referred for Brugada syndrome testing (Kapplinger et al., 2010) and in an individual who presented with fetal bradycardia and went on to develop sick sinus syndrome, conduction disease, and monomorphic ventricular tachycardia in childhood (Marquez et al., 2007; Tan et al., 2007); Not observed at a significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect as the SCN5A-encoded sodium channel current density was reduced 90% compared to wild-type, though late sodium current was increased (Tan et al., 2007); Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 194 amino acids are lost and replaced with 9 incorrect amino acids and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 18361072, 26392562, 17897635, 20129283, 29728395) -

Brugada syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jan 08, 2024

This variant deletes 4 nucleotides in exon 28 of the SCN5A gene, creating a frameshift and premature translation stop signal in the last exon. This variant is expected to disrupt the C-terminal region. This region has been reported to be critical to sodium channel function (PMID: 16686678, 16798729). A functional study has shown that this variant causes a reduced peak channel current in transfected HEK293 cells when compared to wild type (PMID: 17897635). This variant has been reported in an individual suspected of having Brugada syndrome (PMID: 20129283). This variant, annotated as p.Leu1821fs*10, has also been reported in a young individual with a diagnosis of primary electrical disease with mixed arrhythmogenic phenotypes, including sick sinus syndrome, progressive cardiac conduction disease (PCCD), sustained monomorphic ventricular tachycardia, and sudden cardiac death (PMID: 17897635, 35052356). Three relatives of this proband were reported to be symptomatic carriers affected with PCCD while three other relatives were asymptomatic carriers. This variant has been identified in 1/249656 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 27, 2024

The c.5464_5467delTCTG variant, located in coding exon 27 of the SCN5A gene, results from a deletion of 4 nucleotides between positions 5464 and 5467, causing a translational frameshift with a predicted alternate stop codon (p.E1823Hfs*10). This alteration occurs at the 3' terminus of theSCN5A gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 193 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This alteration has been reported in individuals with concerns for Brugada syndrome (Márquez MF et al. Arch Cardiol Mex. 2007;77(4):284-7; Tan BH et al. Cardiovasc Res. 2007;76(3):409-17; Kapplinger JD et al. Heart Rhythm. 2010;7(1):33-46; Ambry internal data). In addition, one functional study reported this variant to result in altered channel function consistent with a loss-of-function effect (Tan BH et al. Cardiovasc Res. 2007;76(3):409-17). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Cardiac arrhythmia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Nov 13, 2023

This variant deletes 4 nucleotides in exon 28 of the SCN5A gene, creating a frameshift and premature translation stop signal in the last exon. This variant is expected to disrupt the C-terminal region. This region has been reported to be critical to sodium channel function (PMID: 16686678, 16798729). A functional study has shown that this variant causes a reduced peak channel current in transfected HEK293 cells when compared to wild type (PMID: 17897635). This variant has been reported in an individual suspected of having Brugada syndrome (PMID: 20129283). This variant, annotated as p.Leu1821fs*10, has also been reported in a young individual with a diagnosis of primary electrical disease with mixed arrhythmogenic phenotypes, including sick sinus syndrome, progressive cardiac conduction disease (PCCD), sustained monomorphic ventricular tachycardia, and sudden cardiac death (PMID: 17897635, 35052356). Three relatives of this proband were reported to be symptomatic carriers affected with PCCD while three other relatives were asymptomatic carriers. This variant has been identified in 1/249656 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely 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: rs794728924; hg19: chr3-38592395;