Submissions for variant NM_006949.4(STXBP2):c.49G>A (p.Gly17Arg)

gnomAD frequency: 0.00270  dbSNP: rs146165014

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000251651	SCV000311681	likely benign	not specified		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000647335	SCV000769125	benign	Familial hemophagocytic lymphohistiocytosis 5	2025-02-03	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000251651	SCV000855548	likely benign	not specified	2017-07-20	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000647335	SCV001530600	uncertain significance	Familial hemophagocytic lymphohistiocytosis 5	2018-03-02	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx	RCV001566927	SCV001790517	uncertain significance	not provided	2021-02-18	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262899	SCV002543000	uncertain significance	Autoinflammatory syndrome	2016-12-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000251651	SCV002766340	likely benign	not specified	2022-11-17	criteria provided, single submitter	clinical testing	Variant summary: STXBP2 c.49G>A (p.Gly17Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0007 in 251462 control chromosomes, predominantly at a frequency of 0.0098 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 4 fold of the estimated maximal predicted allele frequency for a pathogenic variant in STXBP2 causing Familial Hemophagocytic Lymphohistiocytosis phenotype (0.0022), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.49G>A in individuals affected with Familial Hemophagocytic Lymphohistiocytosis and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=3) and benign/likely benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign.
Genetic Services Laboratory, University of Chicago	RCV000251651	SCV003840091	uncertain significance	not specified	2022-11-28	no assertion criteria provided	clinical testing	DNA sequence analysis of the STXBP2 gene demonstrated a sequence change, c.49G>A, in exon 2 that results in an amino acid change, p.Gly17Arg. This sequence change does not appear to have been previously described in individuals with STXBP2-related disorders. This sequence change has been described in the gnomAD database with a frequency of 0.94% in the African subpopulation and 0.09% in the overall population (dbSNP rs146165014). The p.Gly17Arg change affects a highly conserved amino acid residue located in a domain of the STXBP2 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Gly17Arg substitution. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Gly17Arg change remains unknown at this time.