ClinVar Miner

Submissions for variant NM_006949.4(STXBP2):c.1214G>A (p.Arg405Gln)

gnomAD frequency: 0.00002  dbSNP: rs773360200
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000647328 SCV000769118 pathogenic Familial hemophagocytic lymphohistiocytosis 5 2023-11-24 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 405 of the STXBP2 protein (p.Arg405Gln). This variant is present in population databases (rs773360200, gnomAD 0.02%). This missense change has been observed in individuals with hemophagocytic lymphohistiocytosis (PMID: 19804848, 20798128, 23382066, 24194549, 28353193). This variant is also known as c.1205G>A. ClinVar contains an entry for this variant (Variation ID: 538148). 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). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Arg405 amino acid residue in STXBP2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19804848, 28353193). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003226346 SCV003923006 pathogenic Familial hemophagocytic lymphohistiocytosis 2023-03-02 criteria provided, single submitter clinical testing Variant summary: STXBP2 c.1214G>A (p.Arg405Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 250548 control chromosomes (gnomAD). c.1214G>A has been reported in the literature in multiple individuals affected with Familial Hemophagocytic Lymphohistiocytosis (examples: Cetica_2010, Pagel_2012, and Zhang_2020). These data indicate that the variant is very likely to be associated with disease. One clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV000647328 SCV004205639 likely pathogenic Familial hemophagocytic lymphohistiocytosis 5 2023-06-15 criteria provided, single submitter clinical testing
OMIM RCV000647328 SCV001761168 pathogenic Familial hemophagocytic lymphohistiocytosis 5 2021-07-24 no assertion criteria provided literature only

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