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

gnomAD frequency: 0.00001  dbSNP: rs1193962006

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000578998	SCV000680863	likely pathogenic	not provided	2024-09-17	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	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.
Ambry Genetics	RCV004984988	SCV005500017	uncertain significance	Cardiovascular phenotype	2024-09-27	criteria provided, single submitter	clinical testing	The p.E66* variant (also known as c.196G>T), located in coding exon 2 of the SCN1B gene, results from a G to T substitution at nucleotide position 196. This changes the amino acid from a glutamic acid to a stop codon within coding exon 2. Although biallelic loss of function alterations in SCN1B have been associated with autosomal recessive SCN1B-related developmental and epileptic encehpalopathy, haploinsufficiency for SCN1B has not been clearly established as a mechanism of disease for autosomal dominant SCN1B-related epilepsy. Based on the supporting evidence, this variant is expected to be causative of autosomal recessive SCN1B-related developmental and epileptic encehpalopathy when present along with a second pathogenic variant on the other allele; however, its clinical significance for autosomal dominant SCN1B-related epilepsy is unclear.