ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.5464_5467del (p.Glu1823fs) (rs794728924)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183167 SCV000235583 pathogenic not provided 2017-04-10 criteria provided, single submitter clinical testing The c.5464_5467delTCTG variant in the SCN5A gene has been reported 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). Interestingly, in vitro functional analysis showed that, in the presence of c.5464_5467delTCTG, SCN5A-encoded sodium channel current density was reduced 90% compared to wild-type, though late sodium current was increased (Tan et al., 2007). Therefore, the precise mechanism underlying this proband's propensity to develop sick sinus syndrome and monomorphic ventricular tachycardia, but not Brugada syndrome, remained unknown. Of note, family studies showed that, of six asymptomatic relatives also harboring this variant, only two showed mild EKG phenotypes. The reason for intrafamilial phenotype variation was not able to be explained by this study, though it was noted that the majority of these relatives were female, which is consistent with a reportedly male predominance for loss-of-function variants in SCN5A-associated Brugada syndrome. Furthermore, sick sinus syndrome is thought to be an autosomal recessive disease, and a second SCN5A variant, though not detected by the authors, cannot be ruled out. This variant was subsequently reported in one individual referred for Brugada syndrome testing due to a clinical suspicion for Brugada syndrome (Kapplinger et al., 2010). This variant causes a shift in reading frame starting at codon glutamic acid 1823, changing it to a histidine, and creating a premature stop codon at position 10 of the new reading frame, denoted p.Glu1823HisfsX10. This pathogenic variant is expected to result in an abnormal, truncated protein product. Other downstream frameshift and nonsense variants in the SCN5A gene have been reported in Human Gene Mutation Database in association with SCN5A-related disease (Stenson et al., 2014). Lastly, the c.5464_5467delTCTG variant has not been observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Ambry Genetics RCV000242251 SCV000320360 likely pathogenic Cardiovascular phenotype 2017-09-22 criteria provided, single submitter clinical testing Rarity in general population databases (dbsnp, esp, 1000 genomes);Deficient protein function in appropriate functional assay(s);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Other data supporting pathogenic classification
Invitae RCV000525938 SCV000637180 pathogenic Brugada syndrome 2019-12-11 criteria provided, single submitter clinical testing 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, it is expected to disrupt the last 194 amino acids of the SCN5A protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with sick sinus syndrome and ventricular tachycardia (PMID: 18361072). ClinVar contains an entry for this variant (Variation ID: 201573). Experimental studies have shown that this sequence change produced a significant change in channel current density, a voltage shift in activation and a negative shift in inactivation and enhanced intermediate inactivation with reduced peak and early sodium currents and an increase in late sodium current (PMID: 17897635). This variant disrupts the p.His1849 amino acid residue in SCN5A. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 26392562), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000183167 SCV000924941 likely pathogenic not provided 2017-07-24 no assertion criteria provided provider interpretation 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.

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