Submissions for variant NM_006949.4(STXBP2):c.914A>G (p.Glu305Gly)

gnomAD frequency: 0.00015  dbSNP: rs370890802

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000281145	SCV000415681	uncertain significance	Familial hemophagocytic lymphohistiocytosis	2016-06-14	criteria provided, single submitter	clinical testing
Invitae	RCV000927651	SCV001073239	likely benign	Familial hemophagocytic lymphohistiocytosis 5	2024-01-28	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001821004	SCV002065234	uncertain significance	not specified	2021-11-10	criteria provided, single submitter	clinical testing	DNA sequence analysis of the STXBP2 gene demonstrated a sequence change, c.914A>G, in exon 11 that results in an amino acid change, p.Glu305Gly. This sequence change has been described in the gnomAD database with a frequency of 0.55% in the Ashkenazi Jewish subpopulation (dbSNP rs370890802). The p.Glu305Gly change affects a moderately conserved amino acid residue located in a domain of the STXBP2 protein that is known to be functional. The p.Glu305Gly substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change does not appear to have been previously described in individuals with STXBP2-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Glu305Gly change remains unknown at this time.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001821004	SCV004021064	uncertain significance	not specified	2023-06-28	criteria provided, single submitter	clinical testing	Variant summary: STXBP2 c.914A>G (p.Glu305Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00028 in 250586 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in STXBP2 causing Familial Hemophagocytic Lymphohistiocytosis (0.00028 vs 0.0022), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.914A>G in individuals affected with Familial Hemophagocytic Lymphohistiocytosis and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submitters have assessed the variant since 2014: two classified the variant as uncertain significance and one as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003922410	SCV004750362	likely benign	STXBP2-related disorder	2023-05-24	criteria provided, single submitter	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).