Submissions for variant NM_006949.4(STXBP2):c.1586G>C (p.Arg529Pro)

dbSNP: rs35490401

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000363044	SCV000415691	uncertain significance	Familial hemophagocytic lymphohistiocytosis	2016-06-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000529971	SCV000648532	likely benign	Familial hemophagocytic lymphohistiocytosis 5	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV001753791	SCV001985768	uncertain significance	not provided	2024-11-14	criteria provided, single submitter	clinical testing	Reported as an apparently homozygous variant in an individual with hemophilia A, but no additional phenotypic information was provided on this individual beyond the bleeding phenotype (PMID: 34050687); Identified in the heterozygous state in patients in the published literature with suspected familial hemophagocytic lymphohistiocytosis or a suspected bleeding disorder, but no variant was identified on the other allele (PMID: 24916509, 32935436, 36706356); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32256442, 36706356, 32935436, 24916509, 34050687, 36588876)
Genetic Services Laboratory, University of Chicago	RCV001821007	SCV002066027	uncertain significance	not specified	2019-08-15	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002263597	SCV002542991	uncertain significance	Autoinflammatory syndrome	2017-03-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001821007	SCV002570832	uncertain significance	not specified	2023-11-16	criteria provided, single submitter	clinical testing	Variant summary: STXBP2 c.1586G>C (p.Arg529Pro) 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 0.0014 in 247752 control chromosomes, predominantly at a frequency of 0.0024 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in STXBP2 causing Familial Hemophagocytic Lymphohistiocytosis (0.0014 vs 0.0022), allowing no conclusion about variant significance. c.1586G>C has been reported in the literature in heterozygous individuals with clinically-suspected Familial Hemophagocytic Lymphohistiocytosis who were also heterozygous for a variant in PRF1 (e.g. Zhang_2014, Noori_2023). The variant was also found in a homozygous individual with haemophilia A without strong evidence for causality (Carrel_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Hemophagocytic Lymphohistiocytosis. One publication reports experimental evidence evaluating an impact on protein function, suggesting normal cytotoxic activity of CD8+ T and NK cells in vitro, however, it does not allow convincing conclusions about the variant effect in disease (Noori_2023). The following publications have been ascertained in the context of this evaluation (PMID: 34050687, 36706356, 24916509). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as uncertain significance (n=7) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Population Bio, Inc.	RCV001753791	SCV002572504	association	not provided	2022-08-30	criteria provided, single submitter	case-control	STXBP2 variant c.1586G>C (rs35490401) is associated with Progressive multifocal leukoencephalopathy (PML, ORPHA:217260).
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001821007	SCV002761038	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV001753791	SCV004224552	uncertain significance	not provided	2022-09-30	criteria provided, single submitter	clinical testing
Birmingham Platelet Group; University of Birmingham	RCV001270501	SCV001450800	uncertain significance	Abnormal bleeding; Thrombocytopenia	2020-05-01	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV003401347	SCV004104363	likely benign	STXBP2-related disorder	2024-02-20	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).