ClinVar Miner

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

dbSNP: rs1375857363
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Total submissions: 3
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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)
Invitae RCV001215961 SCV001387731 pathogenic Brugada syndrome 5 2023-12-13 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.

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