Submissions for variant NM_001040151.2(SCN3B):c.29T>C (p.Leu10Pro)

gnomAD frequency: 0.00036  dbSNP: rs121918282

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000171567	SCV000050611	uncertain significance	Brugada syndrome	2018-04-05	criteria provided, single submitter	research
GeneDx	RCV000171069	SCV000223633	uncertain significance	not provided	2024-11-19	criteria provided, single submitter	clinical testing	Identified in patients with arrhythmia referred for genetic testing at GeneDx and reported in association with Brugada syndrome, atrial fibrillation, prolonged QT interval, and sudden unexplained infant death syndrome in published literature (PMID: 20031595, 21051419, 25650408, 25757662, 25691686, 23861362); In silico analysis indicates that this missense variant does not alter protein structure/function; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (PMID: 25741868); This variant is associated with the following publications: (PMID: 24667784, 22284586, 25757662, 23414114, 24055113, 24144883, 26728597, 25668026, 25650408, 21051419, 25691686, 20558140, 36362949, 34572065, 35083300, 31961030, 35385795, 35456365, LauK2016[Abstract], 32684122, 36354758, 34495297, 20031595, 23257389, 34867379, 30821013, 31019283, 31043699, 29247119, 38450374, 23861362)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000220802	SCV000272404	uncertain significance	not specified	2015-01-23	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Leu10Pro vari ant in SCN3B has been reported in 1 individual with Brugada syndrome and 1 indiv idual with atrial fibrillation (Hu 2009, Olesen 2011, Olesen 2014). In addition, this variant has been identified in 19/66726 of European chromosomes by the Exo me Aggregation Consortium (ExAC, http://exac.broadinstitute.org/; dbSNP 12191828 2). In vitro functional studies provide some evidence that this variant may impa ct protein function (Hu 2009, Olesen 201), though these types of assays may not accurately represent biological function. Leucine (Leu) at position 10 is not co nserved in mammals with 3 mammals (gibbon, hedgehog, and shrew) carrying a proli ne (Pro) at this position, raising the possibility that this change may be toler ated. In summary, although the clinical significance of the p.Leu10Pro variant is uncertain it is less likely disease causing.
Ambry Genetics	RCV000250087	SCV000319008	likely benign	Cardiovascular phenotype	2022-07-28	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000002574	SCV000959538	uncertain significance	Brugada syndrome 7	2025-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 10 of the SCN3B protein (p.Leu10Pro). This variant is present in population databases (rs121918282, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of SCN3B-related conditions (PMID: 20031595, 21051419, 22284586, 25650408, 25757662, 29247119, 31043699). ClinVar contains an entry for this variant (Variation ID: 2470). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The proline amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects SCN3B function (PMID: 20031595, 21051419, 23257389). 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.
AiLife Diagnostics, AiLife Diagnostics	RCV000171069	SCV002501581	uncertain significance	not provided	2021-06-28	criteria provided, single submitter	clinical testing
OMIM	RCV000002574	SCV000022732	pathogenic	Brugada syndrome 7	2011-03-01	flagged submission	literature only
OMIM	RCV000128811	SCV000172469	pathogenic	Atrial fibrillation, familial, 16	2011-03-01	flagged submission	literature only
GeneReviews	RCV000002574	SCV000188925	not provided	Brugada syndrome 7		no assertion provided	literature only
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000002574	SCV000883102	likely pathogenic	Brugada syndrome 7	2018-11-21	flagged submission	clinical testing