Submissions for variant NM_001037.5(SCN1B):c.396C>G (p.Tyr132Ter)

dbSNP: rs181115510

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000498527	SCV000590134	uncertain significance	not provided	2017-06-01	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the SCN1B gene. The Y132X variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The Y132X variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The Y132X nonsense variant in the SCN1B gene is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. However, loss of function variants in the SCN1B gene have not been reported in Human Gene Mutation Database in association with disease (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002524082	SCV003002642	pathogenic	Brugada syndrome 5	2024-04-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr132*) in the SCN1B gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 137 amino acid(s) of the SCN1B protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SCN1B-related conditions. ClinVar contains an entry for this variant (Variation ID: 432412). This variant disrupts a region of the SCN1B protein in which other variant(s) (p.Trp179*) have been determined to be pathogenic (PMID: 18464934; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.