Submissions for variant NM_001037.5(SCN1B):c.374G>A (p.Arg125His)

gnomAD frequency: 0.00001  dbSNP: rs759839781

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000171061	SCV000223625	uncertain significance	not provided	2014-09-19	criteria provided, single submitter	clinical testing	p.Arg125His (CGC>CAC): c.374 G>A in exon 3 of the SCN1B gene (NM_001037.4). The R125H variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution alters a highly conserved position in the predicted extracellular domain of the SCN1B protein and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, the R125H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Non-conservative amino acid substitutions in same residue (R125C, R125L) have been reported in association with SCN1B-related disorders (Patino et al., 2009; Fendri-Kriaa et al., 2011). Therefore, based on the currently available information, it is unclear whether the R125H variant is a pathogenic mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).
Invitae	RCV000690875	SCV000818604	uncertain significance	Brugada syndrome 5	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 125 of the SCN1B protein (p.Arg125His). This variant is present in population databases (rs759839781, gnomAD 0.0008%). This missense change has been observed in individual(s) with Dravet syndrome and/or epilepsy (PMID: 36011376; Invitae). ClinVar contains an entry for this variant (Variation ID: 190881). 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 disruptive. This variant disrupts the p.Arg125 amino acid residue in SCN1B. Other variant(s) that disrupt this residue have been observed in individuals with SCN1B-related conditions (PMID: 19710327, 28681755), which suggests that this may be a clinically significant amino acid residue. 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.
Fulgent Genetics, Fulgent Genetics	RCV002485077	SCV002775398	uncertain significance	Generalized epilepsy with febrile seizures plus, type 1; Brugada syndrome 5; Atrial fibrillation, familial, 13; Developmental and epileptic encephalopathy, 52	2021-07-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235089	SCV003934267	uncertain significance	not specified	2023-05-02	criteria provided, single submitter	clinical testing	Variant summary: SCN1B c.374G>A (p.Arg125His) results in a non-conservative amino acid change located in the Immunoglobulin V-set domain (IPR013106) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251484 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.374G>A has been reported in the literature in an individual affected with epilepsy (example: Blazekovic_2022). 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. Other variants affecting the same amino acid is reported in association with epilepsy in HGMD. The following publication have been ascertained in the context of this evaluation (PMID: 36011376). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=2) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	RCV001770132	SCV002011708	likely pathogenic	Atrial fibrillation, familial, 13	2021-09-20	no assertion criteria provided	clinical testing