Submissions for variant NM_000335.5(SCN5A):c.2150C>T (p.Pro717Leu)

gnomAD frequency: 0.00001  dbSNP: rs199473149

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000998023	SCV000760284	uncertain significance	not provided	2021-02-24	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has been observed in an individual with Brugada syndrome (PMID: 30193851), an individual with AV node disease (PMID: 26746457), and an individual referred for Brugada syndrome genetic testing (PMID: 20129283). ClinVar contains an entry for this variant (Variation ID: 67717). This variant is present in population databases (rs199473149, ExAC 0.009%). This sequence change replaces proline with leucine at codon 717 of the SCN5A protein (p.Pro717Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine.
GeneDx	RCV000998023	SCV001794137	uncertain significance	not provided	2019-04-15	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in one patient from a cohort of individuals with suspected Brugada syndrome; patient-specific data were not provided (Kapplinger et al., 2010); This variant is associated with the following publications: (PMID: 30193851, 24168886, 25348405, 22581653, 20129283, 24136861, 23414114)
Dr. med. U. Finckh, Human Genetics, Eurofins MVZ	RCV003234768	SCV003932846	uncertain significance	Brugada syndrome 1		criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003996527	SCV004823978	uncertain significance	Cardiac arrhythmia	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 717 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in three individual affected with Brugada syndrome (PMID: 24136861, 30193851, 36516610), in another individual suspected of having Brugada syndrome (PMID: 20129283), and in an arrhythmia case (PMID: 26746457). This variant has been identified in 2/249294 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058484	SCV000090004	not provided	Brugada syndrome		no assertion provided	literature only	This variant has been reported as associated with Brugada syndrome in the following publications (PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.