Submissions for variant NM_001032221.6(STXBP1):c.703C>G (p.Arg235Gly)

dbSNP: rs796053359

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000549629	SCV000633904	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2020-07-17	criteria provided, single submitter	clinical testing	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 observed in individual(s) with STXBP1-related conditions (PMID: 29761117, 26865513). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 207455). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glycine at codon 235 of the STXBP1 protein (p.Arg235Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant disrupts the p.Arg235 amino acid residue in STXBP1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26865513, 25533962, Invitae). 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.
Ambry Genetics	RCV002372156	SCV002667928	uncertain significance	Inborn genetic diseases	2015-12-15	criteria provided, single submitter	clinical testing	The p.R235G variant (also known as c.703C>G), located in coding exon 9 of the STXBP1 gene, results from a C to G substitution at nucleotide position 703. The arginine at codon 235 is replaced by glycine, an amino acid with dissimilar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. 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 p.R235G remains unclear.
Johns Hopkins Genomics, Johns Hopkins University	RCV003150811	SCV003839072	likely pathogenic	Developmental and epileptic encephalopathy, 4	2023-02-01	criteria provided, single submitter	clinical testing	This STXBP1 variant (rs796053359) is absent from a large population dataset and has been reported in ClinVar. The resulting amino acid change occurs in a residue with a previously reported alternate pathogenic missense variant. Two bioinformatic tools queried predict that this substitution would be damaging, and the arginine residue at this position is strongly conserved across the vertebrate species assessed. Bioinformatic analysis predicts that this missense variant would not affect normal exon 9 splicing, although this has not been confirmed experimentally to our knowledge. Two unrelated cases with this variant have been reported that share a similar clinical presentation, including ataxia, wide-based gait, intention tremor, and intellectual disability without epilepsy. This variant was detected in the paternal sample used for analysis. We consider c.703C>G (p.Arg235Gly) to be likely pathogenic.
Duke University Health System Sequencing Clinic, Duke University Health System	RCV003150811	SCV003919039	pathogenic	Developmental and epileptic encephalopathy, 4	2023-04-20	criteria provided, single submitter	research