Submissions for variant NM_001037.5(SCN1B):c.38T>C (p.Leu13Pro)

gnomAD frequency: 0.00001  dbSNP: rs786205834

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766768	SCV000223614	uncertain significance	not provided	2022-12-05	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Genetic Services Laboratory, University of Chicago	RCV000192329	SCV000248799	uncertain significance	not specified	2015-04-16	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000192329	SCV000615051	uncertain significance	not specified	2017-07-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000687916	SCV000815509	uncertain significance	Brugada syndrome 5	2023-12-24	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 13 of the SCN1B protein (p.Leu13Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of SCN1B-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 190870). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.
Ambry Genetics	RCV002316985	SCV000851316	uncertain significance	Cardiovascular phenotype	2018-11-17	criteria provided, single submitter	clinical testing	The p.L13P variant (also known as c.38T>C), located in coding exon 1 of the SCN1B gene, results from a T to C substitution at nucleotide position 38. The leucine at codon 13 is replaced by proline, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV000765437	SCV000896726	uncertain significance	Generalized epilepsy with febrile seizures plus, type 1; Brugada syndrome 5; Atrial fibrillation, familial, 13; Developmental and epileptic encephalopathy, 52	2018-10-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000192329	SCV001437234	uncertain significance	not specified	2020-09-09	criteria provided, single submitter	clinical testing	Variant summary: SCN1B c.38T>C (p.Leu13Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 7.1e-06 in 140328 control chromosomes (gnomAD v3). 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.38T>C in individuals affected with SCN1B-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.