ClinVar Miner

Submissions for variant NM_006949.4(STXBP2):c.1385C>T (p.Pro462Leu)

gnomAD frequency: 0.00001  dbSNP: rs573587268
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV001820702 SCV002070325 uncertain significance not specified 2020-07-24 criteria provided, single submitter clinical testing DNA sequence analysis of the STXBP2 gene demonstrated a sequence change, c.1385C>T, in exon 16 that results in an amino acid change, p.Pro462Leu. This sequence change does not appear to have been previously described in patients with STXBP2-related disorders and has been described in the gnomAD database in 3 individuals, with a low overall population frequency of 0.001% (dbSNP rs573587268). The p.Pro462Leu change affects a poorly conserved amino acid residue located in a domain of the STXBP2 protein that is known to be functional. The p.Pro462Leu substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Pro462Leu change remains unknown at this time.
Labcorp Genetics (formerly Invitae), Labcorp RCV001869738 SCV002191775 uncertain significance Familial hemophagocytic lymphohistiocytosis 5 2021-09-01 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 462 of the STXBP2 protein (p.Pro462Leu). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs573587268, ExAC 0.04%). This variant has not been reported in the literature in individuals affected with STXBP2-related conditions. 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 tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV004770216 SCV005377173 uncertain significance not provided 2023-11-13 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

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