Submissions for variant NM_006949.4(STXBP2):c.1621G>A (p.Gly541Ser)

dbSNP: rs61736587

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000519780	SCV000617868	pathogenic	not provided	2025-02-19	criteria provided, single submitter	clinical testing	Published functional studies demonstrate the variant disrupts association of the protein with syntaxin 11, and functional assays show defective degranulation and cellular cytotoxicity (PMID: 20798128); 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: 20823128, 26320718, 23687090, 24194549, 32542393, 31589614, 35020838, 33162974, 20798128, 36706356, 20558610, 38259611, 22451424, Podvin2024[Preprint], 37647632)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000024317	SCV000822990	pathogenic	Familial hemophagocytic lymphohistiocytosis 5	2025-02-03	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 541 of the STXBP2 protein (p.Gly541Ser). This variant is present in population databases (rs61736587, gnomAD 0.05%). This missense change has been observed in individuals with hemophagocytic lymphohistiocytosis type 5 (PMID: 20558610, 20798128, 20823128). ClinVar contains an entry for this variant (Variation ID: 30219). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt STXBP2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects STXBP2 function (PMID: 20798128, 24194549). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV000519780	SCV000927257	pathogenic	not provided	2017-05-10	criteria provided, single submitter	clinical testing
Mendelics	RCV000024317	SCV001140968	pathogenic	Familial hemophagocytic lymphohistiocytosis 5	2019-05-28	criteria provided, single submitter	clinical testing
3billion, Medical Genetics	RCV000024317	SCV002521170	pathogenic	Familial hemophagocytic lymphohistiocytosis 5	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.023%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 20798128). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97; 3Cnet: 0.96). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic with strong evidence (ClinVar ID: VCV000030219). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262571	SCV002542993	pathogenic	Autoinflammatory syndrome	2022-04-26	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000024317	SCV002761706	likely pathogenic	Familial hemophagocytic lymphohistiocytosis 5	2021-09-03	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000024317	SCV003799015	likely pathogenic	Familial hemophagocytic lymphohistiocytosis 5	2022-12-08	criteria provided, single submitter	clinical testing	PS3, PM2, PP3
Revvity Omics, Revvity	RCV000024317	SCV003819765	pathogenic	Familial hemophagocytic lymphohistiocytosis 5	2022-01-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226166	SCV003923007	pathogenic	Familial hemophagocytic lymphohistiocytosis	2023-03-27	criteria provided, single submitter	clinical testing	Variant summary: STXBP2 c.1621G>A (p.Gly541Ser) 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 0.00023 in 248156 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in STXBP2 causing Familial Hemophagocytic Lymphohistiocytosis (0.00023 vs 0.0022), allowing no conclusion about variant significance. c.1621G>A has been reported in the literature as biallelic homozygous or compound heterozygous genotypes in multiple individuals affected with Familial Hemophagocytic Lymphohistiocytosis (example, Cetica_2010, Pagel_2012). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Cetica_2012). The most pronounced variant effect results in a defective protein and by defective cytotoxicity by T lymphocytes. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000024317	SCV004205622	pathogenic	Familial hemophagocytic lymphohistiocytosis 5	2024-03-21	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000024317	SCV005648854	pathogenic	Familial hemophagocytic lymphohistiocytosis 5	2024-03-30	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000519780	SCV005872320	pathogenic	not provided	2025-03-04	criteria provided, single submitter	clinical testing
OMIM	RCV000024317	SCV000045608	pathogenic	Familial hemophagocytic lymphohistiocytosis 5	2010-09-01	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV003398562	SCV004119961	pathogenic	STXBP2-related disorder	2024-06-28	no assertion criteria provided	clinical testing	The STXBP2 c.1621G>A variant is predicted to result in the amino acid substitution p.Gly541Ser. This variant was reported in the homozygous state in a patient with familial hemophagocytic lymphohistiocytosis (FHL) who lacked variants in the PRF1, UNC13D, and STX11 genes (Cetica et al. 2010. PubMed ID: 20798128). It has also been reported along with a second STXBP2 variant in other patients with FHL (Meeths et al. 2010. PubMed ID: 20558610; Rohr et al. 2010. PubMed ID: 20823128). Functional data in Cetica et al. suggest the p.Gly541Ser substitution affects binding of the STXBP2 protein to its effectors. This variant is reported in 0.047% of alleles in individuals of European (Non-Finnish) descent in gnomAD. It has been interpreted as pathogenic by multiple submitters to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/30219). Taken together, this variant is interpreted as pathogenic.