Submissions for variant NM_001032221.6(STXBP1):c.1651C>T (p.Arg551Cys)

dbSNP: rs796053373

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000189623	SCV000243268	pathogenic	not provided	2021-10-25	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; The majority of missense variants in this gene are considered pathogenic (HGMD); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26514728, 29186148, 23409955, 22495311, 27069701, 26865513, 28191890, 29655203, 31130284, 28714951, 31981491, 33219223, 31175295, 31785789)
Athena Diagnostics	RCV000189623	SCV000615518	pathogenic	not provided	2017-01-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001071757	SCV001237078	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2024-05-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 551 of the STXBP1 protein (p.Arg551Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with early-onset epileptic encephalopathy (PMID: 23409955, 26865513). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 207440). 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.Arg551 amino acid residue in STXBP1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26865513; 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.
CeGaT Center for Human Genetics Tuebingen	RCV000189623	SCV001246984	pathogenic	not provided	2020-01-01	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000415936	SCV001428885	pathogenic	Developmental and epileptic encephalopathy, 4	2018-07-17	criteria provided, single submitter	clinical testing
Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli	RCV001420235	SCV001622655	pathogenic	See cases	2021-04-26	criteria provided, single submitter	clinical testing	PS3_strong;PS5_strong;PM1_moderate;PM2_supporting;PM5_moderate;PM6_moderate;PP2_supporting;PP3_supporting
Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine	RCV003126574	SCV003803759	pathogenic	Developmental disorder	2020-03-12	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000415936	SCV003921960	pathogenic	Developmental and epileptic encephalopathy, 4	2020-10-19	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.3, 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 STXBP1-related epileptic encephalopathy. (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) 0600 - Variant is located in the annotated Sec1 family domain (NCBI, PDB). (I) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Alternative changes at the same residue, to glycine, histidine, leucine, proline and serine, have previously been classified as pathogenic in individuals with STXBP1-related disorders (ClinVar, Decipher). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported as pathogenic in multiple individuals with STXBP1-related epileptic encephalopathy, and is commonly found to be de novo (ClinVar, Decipher, PMID: 26865513). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies in a worm model resulted in impaired locomotion, consistent with a loss of function (PMID: 32112430). (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
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000415936	SCV004014018	pathogenic	Developmental and epileptic encephalopathy, 4	2023-02-20	criteria provided, single submitter	clinical testing	PS3, PM1, PM2, PM5, PP3, PP5
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000415936	SCV004808235	pathogenic	Developmental and epileptic encephalopathy, 4	2024-03-29	criteria provided, single submitter	clinical testing
3billion	RCV000415936	SCV005905933	pathogenic	Developmental and epileptic encephalopathy, 4	2023-12-01	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.97 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.97 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000207440 /PMID: 22495311 /3billion dataset). Different missense changes at the same codon (p.Arg551His, p.Arg551Leu, p.Arg551Pro, p.Arg551Ser) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000207439, VCV000207441, VCV000373210, VCV000566474 /PMID: 26865513, 29655203). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
GeneReviews	RCV000415936	SCV000494043	not provided	Developmental and epileptic encephalopathy, 4		no assertion provided	literature only
GenomeConnect - Simons Searchlight	RCV001265516	SCV001443660	pathogenic	Infantile epilepsy syndrome	2018-04-06	no assertion criteria provided	provider interpretation	Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-04-06 and interpreted as Pathogenic. The reporting laboratory might also submit to ClinVar. This variant was identified in multiple probands enrolled in Simons Searchlight.