Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001056642 | SCV001221095 | likely pathogenic | Familial hemophagocytic lymphohistiocytosis 5 | 2024-01-18 | 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 334 of the STXBP2 protein (p.Pro334Leu). This variant is present in population databases (rs747031778, gnomAD 0.1%). This missense change has been observed in individual(s) with familial hemophagocytic lymphohistiocytosis type 5 (PMID: 22336081, 22791290, 27379089, 28399723, 29599780). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 852094). 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 STXBP2 protein function with a positive predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on STXBP2 function (PMID: 24194549). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001553694 | SCV001774656 | uncertain significance | not specified | 2024-03-27 | criteria provided, single submitter | clinical testing | Variant summary: STXBP2 c.1001C>T (p.Pro334Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 251474 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in STXBP2 causing Familial Hemophagocytic Lymphohistiocytosis (6.4e-05 vs 0.0022), allowing no conclusion about variant significance. c.1001C>T has been reported in the literature in individuals affected with Familial Hemophagocytic Lymphohistiocytosis, suspected rare inherited bleeding disorders and common variable immunodeficiency (Saltzman_2012, Maffucci_2016, Leine_2017, Lopez_2018), and at-least one of these individuals were reported as a late onset case (Minson_2021). Functional studies report experimental evidence evaluating an impact on protein function and showed no damaging effect of this variant (Hackmann_2013, Fager Ferrari_2017) or 67% of wild-type activity (Noori_2023). Taken together these data suggest that pathogenicity of this variant is evident when the variant in trans is a null allele. The following publications have been ascertained in the context of this evaluation (PMID: 28399723, 24194549, 28748566, 29599780, 30104219, 27379089, 22336081, 34336208, 36706356). ClinVar contains an entry for this variant (Variation ID: 852094). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |
| Baylor Genetics | RCV001056642 | SCV004205633 | likely pathogenic | Familial hemophagocytic lymphohistiocytosis 5 | 2024-03-26 | criteria provided, single submitter | clinical testing | |
| Mayo Clinic Laboratories, |
RCV003480935 | SCV004227674 | likely pathogenic | not provided | 2023-05-16 | criteria provided, single submitter | clinical testing | PM1, PM3, PS3_moderate, PS4_moderate |