ClinVar Genomic variation as it relates to human health

This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 130 of the STXBP2 protein (p.Leu130Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with familial hemophagocytic lymphohistiocytosis (PMID: 22791290). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 579782). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.

This variant has been previously reported in the homozygous state and in the heterozygous state together with a second STXBP2 variant in individuals with symptoms of hemophagocytic lymphohistiocytosis (PMID: 32542393, 22791290). The c.389T>C (p.Leu130Ser) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.003% (1/31360) and thus is presumed to be rare. It affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples showed the mother is negative and the father is heterozygous for this variant. Based on the available evidence, the c.389T>C (p.Leu130Ser) variant is classified as Likely Pathogenic.

Variant summary: STXBP2 c.389T>C (p.Leu130Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. In a structural analysis of of the protein, the variant mapped to the predicted syntaxin and soluble N-ethylmaleimidesensitive factor accessory protein receptor binding sites of Munc18-2 (Hackman_2013). The variant was absent in 251460 control chromosomes. c.389T>C has been reported in the literature in individuals affected with Hemophagocytic Lymphohistiocytosis including one homozygous patient, a compound heterozygous patient with a pathogenic variant on the second allele, and a patient who also carried an exon deletion without phase of the variants specified (AlHawas_2012, Gadoury-Levesque_2020). In experimental studies from a biallelic patient carrying the variant along with a pathogenic variant in trans, Munc18b was undetectable in platelets from the patient, suggesting the variant causes the production of an unstable Munc18b protein. Additionally, platelets from this patient exhibited a severe defect in release from both dense and alpha-granules and ADP/ATP was almost completely absent (Al Hawas_2012). The following publications have been ascertained in the context of this evaluation (PMID: 22791290, 32542393, 24194549). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.

Observed with a partial deletion of the STXBP2 gene in a patient with features of hemophagocytic lymphohistiocytosis in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (PMID: 32542393); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32542393, 22791290, 24194549)