Submissions for variant NM_001037.5(SCN1B):c.448+100G>T

gnomAD frequency: 0.00002  dbSNP: rs779658201

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003387892	SCV000700048	uncertain significance	not specified	2023-09-28	criteria provided, single submitter	clinical testing	Variant summary: SCN1B c.548G>T (p.Trp183Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 247812 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.548G>T has been reported in the literature in an individual who survived a clinically-idiopathic sudden cardiac arrest (Isbister_2021). This report does not provide unequivocal conclusions about association of the variant with SCN1B-Related Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 32931854). One submitter has cited a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470916	SCV002769190	uncertain significance	Developmental and epileptic encephalopathy, 52	2020-05-25	criteria provided, single submitter	clinical testing	A heterozygous missense variant was identified, NM_199037.4(SCN1B):c.548G>T in exon 3 of 3 of the SCN1B gene. This substitution is predicted to create a minor amino acid change from tryptophan to leucine at position 183 of the protein NP_950238.1(SCN1B):p.(Trp183Leu). The tryptophan at this position has low conservation (100 vertebrates, UCSC), but is not situated in a known functional domain. In silico software predicts this variant to be benign (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD population database at a frequency of 0.0004 % (1 heterozygote, 0 homozygotes). The variant has been previously reported as a variant of uncertain significance (VUS) in ClinVar. Based on information available at the time of curation, this variant has been classified as a VARIANT of UNCERTAIN SIGNIFICANCE (VUS) with LOW CLINICAL RELEVANCE. Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Invitae	RCV003767345	SCV004621148	uncertain significance	Brugada syndrome 5	2023-10-22	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan, which is neutral and slightly polar, with leucine, which is neutral and non-polar, at codon 183 of the SCN1B protein (p.Trp183Leu). This variant is present in population databases (rs779658201, gnomAD 0.002%). 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: 496576). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.