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

dbSNP: rs1450434935

Total submissions: 5

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 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 variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Brugada syndrome and/or noncompaction cardiomyopathy (PMID: 19251209, 29447731, 30193851). ClinVar contains an entry for this variant (Variation ID: 1327132). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
KardioGenetik, Herz- und Diabeteszentrum NRW	RCV003394255	SCV004101815	pathogenic	Brugada syndrome 1	2023-10-30	criteria provided, single submitter	clinical testing
GeneDx	RCV003542346	SCV005907056	likely pathogenic	not provided	2024-09-30	criteria provided, single submitter	clinical testing	Identified in patients with Brugada syndrome referred for genetic testing at GeneDx and in published literature (PMID: 19251209, 30193851, 34461752, 20129283); Identified in association with sudden unexpected death in pediatrics (SUDP) and noncompaction cardiomyopathy (NCCM) in published literature; at least one individual harbored additional cardiogenetic variants (PMID: 29447731, 35027292); Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Also known as c.4299delG; This variant is associated with the following publications: (PMID: 29447731, 19251209, 34461752, 20129283, 30193851, 35027292)