ClinVar Miner

Submissions for variant NM_003165.4(STXBP1):c.874C>T (p.Arg292Cys) (rs786205598)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000171427 SCV000243250 pathogenic not provided 2018-10-31 criteria provided, single submitter clinical testing The R292C variant in the STXBP1 gene was previously reported as a de novo pathogenic variant in individuals with epileptic encephalopathy (Stamberger et al., 2016; Saudi et al., 2015). The R292C variant is not observed in large population cohorts (Lek et al., 2016). The R292C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Additionally, a different missense variant in the same codon (R292H) has been reported in association with infantile spasms (Stamberger et al.,2016), supporting the functional importance of this region of the protein.
Genetic Services Laboratory, University of Chicago RCV000502114 SCV000597322 uncertain significance not specified 2013-06-06 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515202 SCV000611324 pathogenic Early infantile epileptic encephalopathy 4 2017-05-18 criteria provided, single submitter clinical testing
Invitae RCV000700520 SCV000829278 pathogenic Early infantile epileptic encephalopathy 2018-06-19 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 variant has been reported to be de novo in individuals affected with early infantile epileptic encephalopathy (PMID: 26865513). 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"). The p.Arg292His and p.Arg292Leu amino acid residues in STXBP1 have been determined to be clinically significant (PMID: 26865513, 26993267, 25356970, Invitae). This suggests that variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Mendelics RCV000515202 SCV001137906 pathogenic Early infantile epileptic encephalopathy 4 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000171427 SCV001246232 pathogenic not provided 2020-03-01 criteria provided, single submitter clinical testing
Developmental Genetics Unit,King Faisal Specialist Hospital & Research Centre RCV000171427 SCV000221625 likely pathogenic not provided no assertion criteria provided research
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.

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