ClinVar Miner

Submissions for variant NM_001037.5(SCN1B):c.196G>T (p.Glu66Ter)

gnomAD frequency: 0.00001  dbSNP: rs1193962006
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000578998 SCV000680863 uncertain significance not provided 2017-08-07 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SCN1B gene. The E66X variant hasnot been published as a pathogenic variant, nor has it been reported as a benign variant to ourknowledge. It was not observed in approximately 6,500 individuals of European and AfricanAmerican ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benignvariant in these populations. The E66X nonsense variant is predicted to cause loss of normalprotein function either through protein truncation or nonsense-mediated mRNA decay. However,nonsense variants have not been reported in the Human Gene Mutation Database in associationwith SCN1B-related disorders (Stenson et al., 2014). Therefore, based on the currently availableinformation, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV001368794 SCV001565205 uncertain significance Brugada syndrome 5 2023-01-06 criteria provided, single submitter clinical testing 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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 488917). This variant has not been reported in the literature in individuals affected with SCN1B-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu66*) in the SCN1B gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 203 amino acid(s) of the SCN1B protein.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV004017681 SCV004847409 likely pathogenic Undetermined early-onset epileptic encephalopathy 2024-01-08 criteria provided, single submitter clinical testing The p.Glu66X variant in SCN1B has not been previously reported in individuals with epilepsy but has been reported by other clinical laboratories in ClinVar (Variation ID 488917). It has also been identified in 0.002% (1/41472) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). This nonsense variant leads to a premature termination codon at position 66, which is predicted to lead to a truncated or absent protein. Biallelic loss of function of the SCN1B gene is has been associated with autosomal recessive epileptic encephalopathy (Patino 2009 PMID: 19710327, Ramadan 2017 PMID: 28218389, Chancey 2023 PMID: 37845033). Please note that this gene is also associated with autosomal dominant epilepsy, however at this time it is unknown if loss of function variants are also implicated in the disease mechanism. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive epileptic encephalopathy. ACMG/AMP Criteria applied: PVS1, PM2_Supporting.

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