Submissions for variant NM_001037.5(SCN1B):c.1A>C (p.Met1Leu)

dbSNP: rs1375857363

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000578768	SCV000681057	uncertain significance	not provided	2023-05-13	criteria provided, single submitter	clinical testing	Initiation codon variant in a gene for which loss-of-function is not 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; This variant is associated with the following publications: (PMID: 24069305, 30660056)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001215961	SCV001387731	pathogenic	Brugada syndrome 5	2024-07-30	criteria provided, single submitter	clinical testing	This sequence change affects the initiator methionine of the SCN1B mRNA. The next in-frame methionine is located at codon 34. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individuals with clinical features of autosomal dominant SCN1B-related conditions (PMID: 30660056; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 489074). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002420551	SCV002724196	uncertain significance	Cardiovascular phenotype	2023-03-10	criteria provided, single submitter	clinical testing	The p.M1? variant (also known as c.1A>C) is located in coding exon 1 of the SCN1B gene, results from an A to C substitution at nucleotide position 1. This alters the methionine residue at the initiation codon (ATG). This variant has been identified in a family with genetic epilepsy with febrile seizures plus (GEFS+); however, not all individuals with seizures tested positive for this variant (Myers KA et al. Epilepsy Res., 2019 02;150:66-69). This amino acid position is conserved on limited sequence alignment. Variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame; however, there is an in-frame methionine 34 amino acids from the initiation site, which may result in N-terminal truncation of unknown functional significance. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987612	SCV004804108	uncertain significance	not specified	2024-01-03	criteria provided, single submitter	clinical testing	Variant summary: SCN1B c.1A>C (p.Met1Leu) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. Two of three in-silico tools predict a benign effect of the variant on protein function. The next downstream in-frame ATG start site is at codon 34 (Exon 2). Other initiation codon variants, as well as variants downstream of the initiation codon variant but upstream of the potential new start codon have been reported in association with SCN1B-related disorders in HGMD, but have not been reported as pathogenic by our lab or in ClinVar. The variant allele was found at a frequency of 1.1e-06 in 927680 control chromosomes (gnomAD v4). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1A>C in individuals affected with SCN1B-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have reported clinical-significance assessments for this variant to ClinVar after 2014 with conflicting interpretations (VUS, n = 2; likely pathogenic, n = 1). Based on the evidence outlined above, the variant was classified as uncertain significance.