ClinVar Miner

Submissions for variant NM_006949.4(STXBP2):c.1430C>T (p.Pro477Leu)

gnomAD frequency: 0.00001  dbSNP: rs121918540
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000008308 SCV000932417 pathogenic Familial hemophagocytic lymphohistiocytosis 5 2024-02-23 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 477 of the STXBP2 protein (p.Pro477Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with hemophagocytic lymphohistiocytosis (PMID: 19804848, 19884660). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7858). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on STXBP2 protein function. Experimental studies have shown that this missense change affects STXBP2 function (PMID: 19804848, 19884660). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity RCV000008308 SCV002021982 pathogenic Familial hemophagocytic lymphohistiocytosis 5 2020-04-21 criteria provided, single submitter clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre RCV000008308 SCV003924323 pathogenic Familial hemophagocytic lymphohistiocytosis 5 2023-05-08 criteria provided, single submitter research
Baylor Genetics RCV000008308 SCV004205629 pathogenic Familial hemophagocytic lymphohistiocytosis 5 2023-12-27 criteria provided, single submitter clinical testing
OMIM RCV000008308 SCV000028515 pathogenic Familial hemophagocytic lymphohistiocytosis 5 2010-09-01 no assertion criteria provided literature only
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City RCV000008308 SCV001133011 pathogenic Familial hemophagocytic lymphohistiocytosis 5 2019-09-15 no assertion criteria provided clinical testing
PreventionGenetics, part of Exact Sciences RCV003924815 SCV004743960 pathogenic STXBP2-related disorder 2023-11-30 no assertion criteria provided clinical testing The STXBP2 c.1430C>T variant is predicted to result in the amino acid substitution p.Pro477Leu. This variant has been reported to be pathogenic in several patients with familial hemophagocytic lymphohistiocytosis (FHL) and may be associated with early onset, severe forms of FHL (zur Stadt et al. 2009. PubMedID: 19804848; Cote et al. 2009, PubMedID: 19884660; Cetica et al. 2010. PubMedID: 20798128). This variant is reported in 0.0052% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as pathogenic.

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