ClinVar Genomic variation as it relates to human health

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

PS2, PM2, PS4

The c.1216C>T;p.(Arg406Cys) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 207431; PMID: 28947817; 28387369; 27171548; 26648591) - PS4. This variant is not present in population databases:rs796053367, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Pathogenic missense variant in this residue have been reported and classified as Pathogenic by ACMG criteria (Clinvar ID: 279904 - c.1217G>A;p.(Arg406His); Clinvar ID: 419223 - c.1217G>T (p.Arg406Leu)) - PM5. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 28387369; 27171548; 26648591)PM6. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is Pathogenic

A different missense substitution at this codon (p.Arg406His) has been determined to be pathogenic (PMID: 20887364, 21762454, 23934111). This suggests that the arginine residue is critical for STXBP1 protein function and that other missense substitutions at this position may also be pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been reported to be de novo in several individuals affected with early-onset epileptic encephalopathy (PMID: 26648591, 28387369) and several individuals affected with Rett-like syndrome (PMID: 28947817, 27171548). ClinVar contains an entry for this variant (Variation ID: 207431). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with cysteine at codon 406 of the STXBP1 protein (p.Arg406Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. For these reasons, this variant has been classified as Pathogenic.

The c.1216C>T (p.R406C) alteration is located in coding exon 14 of the STXBP1 gene. This alteration results from a C to T substitution at nucleotide position 1216, causing the arginine (R) at amino acid position 406 to be replaced by a cysteine (C). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported as a de novo finding in an individual with a history of seizures, profound intellectual disability (ID), ocular wobble, limb spasticity, progressive microcephaly with brain atrophy, and percutaneous endoscopic gastrostomy (Allen, 2015). The c.1216C>T (p.R406C) variant has also been reported as a pathogenic de novo finding in a 2 month old Chinese male with epilepsy and global developmental delay (Zou, 2021). Another alteration at the same codon, c.1217G>A (p.R406H), is a well known pathogenic variant in the STXBP1 gene and has been reported as a de novo finding in several unrelated affected individuals with early onset seizures, severe to profound ID, specific abnormal EEG findings, infantile spasms, spastic quadraplegia, limb hypertonia, ataxic gait, and autistic features (Saitsu, 2010; Mignot, 2011; Epi4k, 2013; Romaniello, 2015; Stamberger, 2016). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

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: 35007884, 28947817, 29390993, 26648591, 28387369, 27171548, 31344879, 31487502, 27864847, 32005694, 32139178, 28191889, 31175295, 33004838, 35851549, 31440721, 34145886, 35190816, 29190809)

Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2017-01-27 and interpreted as Pathogenic. Variant was initially reported on 2013-05-06 by GTR ID of laboratory name 26957. The reporting laboratory might also submit to ClinVar.