ClinVar Genomic variation as it relates to human health

Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 23934111, 23708187, 26633542, 32581362, 32725632, 31175295, 33004838, 31130284)

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 190 of the STXBP1 protein (p.Arg190Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with seizures (PMID: 26633542; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 207418). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt STXBP1 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg190 amino acid residue in STXBP1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23708187, 23934111, 26514728, 26544041). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

The p.R190Q variant (also known as c.569G>A), located in coding exon 7 of the STXBP1 gene, results from a G to A substitution at nucleotide position 569. The arginine at codon 190 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in a subject with epilepsy from a whole exome sequencing cohort (Retterer K et al. Genet. Med., 2016 07;18:696-704). Another alterations affecting the same amino acid, p.R190W (c.568C>T), has also been reported in association with epilepsy (Carvill GL et al. Nat. Genet., 2013 Jul;45:825-30). 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.

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with autosomal dominant developmental and epileptic encephalopathy 4 (DEE, MIM#612164). In addition, gain of function has been shown for a missense variant associated with autosomal recessive DEE (PMID: 31855252). Dominant negative has also been suggested (PMID: 35190816). (I) 0107 - This gene is associated with autosomal dominant disease. Autosomal recessive inheritance has been reported in one family with epilepsy and intellectual disability (PMID: 31855252). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated sec1 domain (DECIPHER). (I) 0703 - Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. p.(Arg190Trp) has been reported as pathogenic by multiple clinical testing laboratories (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in the literature in multiple individuals with seizures or epilepsy, and as de novo in some of them (PMIDs: 36440324, 32725632, 26633542). It has also been reported as pathogenic/likely pathogenic by multiple clinical testing laboratories (ClinVar). One clinical testing laboratory had reported this variant as a VUS, however no compelling evidence was provided against variant pathogenicity (ClinVar). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign