Submissions for variant NM_001032221.6(STXBP1):c.874C>T (p.Arg292Cys)

dbSNP: rs786205598

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Department Of Translational Genomics (developmental Genetics Section), King Faisal Specialist Hospital & Research Centre	RCV000171427	SCV000221625	likely pathogenic	not provided		criteria provided, single submitter	research
GeneDx	RCV000171427	SCV000243250	pathogenic	not provided	2021-10-27	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 29655203, 29933521, 26865513, 26993267, 26112015, 29390993, 31487502, 32139178, 31105003, 31054490, 31031587, 24077912)
Fulgent Genetics, Fulgent Genetics	RCV000515202	SCV000611324	pathogenic	Developmental and epileptic encephalopathy, 4	2017-05-18	criteria provided, single submitter	clinical testing
Invitae	RCV000700520	SCV000829278	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2021-08-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with cysteine at codon 292 of the STXBP1 protein (p.Arg292Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with early infantile epileptic encephalopathy (PMID: 26865513). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 191238). 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: "Benign"; Align-GVGD: "Class C55"). This variant disrupts the p.Arg292 amino acid residue in STXBP1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25356970, 26865513, 26993267). 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.
Mendelics	RCV000515202	SCV001137906	pathogenic	Developmental and epileptic encephalopathy, 4	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000171427	SCV001246232	pathogenic	not provided	2020-03-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001266353	SCV001444527	pathogenic	Inborn genetic diseases	2018-10-11	criteria provided, single submitter	clinical testing
Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris	RCV001640264	SCV001519226	pathogenic	Spastic ataxia	2021-01-04	criteria provided, single submitter	research
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000515202	SCV002557107	pathogenic	Developmental and epileptic encephalopathy, 4	2022-06-24	criteria provided, single submitter	clinical testing	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 developmental and epileptic encephalopathy 4 (MIM#612164). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (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) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. At least three other missense variants have been reported at this residue (ClinVar, DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in at least ten individuals, including de novo events and in patients with STXBP1 -encephalopathy (ClinVar, PMID: 26865513, 32643187). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	RCV003488419	SCV004232649	pathogenic	West syndrome	2023-12-15	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000502114	SCV000597322	uncertain significance	not specified	2013-06-06	flagged submission	clinical testing
GenomeConnect, ClinGen	RCV000509312	SCV000607363	not provided	Early onset epileptic encephalopathy		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
GenomeConnect - Simons Searchlight	RCV001265420	SCV001443546	pathogenic	Infantile epilepsy syndrome	2019-04-15	no assertion criteria provided	provider interpretation	Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2019-04-15 and interpreted as Pathogenic. The reporting laboratory might also submit to ClinVar. This variant was identified in multiple probands enrolled in Simons Searchlight.
Pediatric Department, Xiangya Hospital, Central South University	RCV000515202	SCV001961012	pathogenic	Developmental and epileptic encephalopathy, 4	2020-01-09	no assertion criteria provided	clinical testing