ClinVar Miner

Submissions for variant NM_000335.5(SCN5A):c.4296+1del

dbSNP: rs1450434935
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Robert's Program, Boston Children's Hospital RCV001787415 SCV002030068 likely pathogenic SUDDEN INFANT DEATH SYNDROME 2021-10-01 criteria provided, single submitter research We classify this variant as pathogenic using the following ACMG/AMP criteria: PVS1, PM2
Ambry Genetics RCV002329758 SCV002629689 likely pathogenic Cardiovascular phenotype 2021-07-26 criteria provided, single submitter clinical testing The c.4299+1delG intronic variant, located in intron 23 of the SCN5A gene, results from a deletion of one nucleotide within intron 23 of the SCN5A gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). This variant (also referred to as c.4299delG) has been detected in individuals from Brugada syndrome or cardiac conduction disease cohorts; however, details were limited and reports may overlap (Meregalli PG et al. Heart Rhythm, 2009 Mar;6:341-8; Berthome P et al. Heart Rhythm, 2019 02;16:260-267). This variant also co-occurred with another variant in a cardiac-related gene in a noncompaction cardiomyopathy cohort (van Waning JI et al. J Am Coll Cardiol, 2018 02;71:711-722). This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV003542346 SCV003525426 pathogenic not provided 2022-01-17 criteria provided, single submitter clinical testing This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr1434Metfs*29) in the SCN5A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SCN5A are known to be pathogenic (PMID: 20129283, 22789973). This premature translational stop signal has been observed in individual(s) with Brugada syndrome and/or noncompaction cardiomyopathy (PMID: 19251209, 29447731, 30193851). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 1327132).
KardioGenetik, Herz- und Diabeteszentrum NRW RCV003394255 SCV004101815 pathogenic Brugada syndrome 1 2023-10-30 criteria provided, single submitter clinical testing

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