Submissions for variant NM_006949.4(STXBP2):c.365G>A (p.Arg122His)

gnomAD frequency: 0.00229  dbSNP: rs144914451

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000647332	SCV000769122	benign	Familial hemophagocytic lymphohistiocytosis 5	2025-02-03	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000647332	SCV001295953	benign	Familial hemophagocytic lymphohistiocytosis 5	2017-08-09	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
GeneDx	RCV001756079	SCV001988433	uncertain significance	not provided	2020-11-02	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Reported in the heterozygous state in a patient with hemophagocytic lymphohistiocytosis in published literature (Chen et al., 2018) with no second variant identified; This variant is associated with the following publications: (PMID: 29665027, 25556537)
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002263901	SCV002542531	likely benign	Autoinflammatory syndrome	2020-09-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271545	SCV002556249	likely benign	not specified	2022-06-29	criteria provided, single submitter	clinical testing	Variant summary: STXBP2 c.365G>A (p.Arg122His) 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 0.00063 in 251472 control chromosomes (gnomAD), predominantly at a frequency of 0.0082 within the African or African-American subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 4-fold of the estimated maximal expected allele frequency for a pathogenic variant in STXBP2 causing Familial Hemophagocytic Lymphohistiocytosis (0.0022), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.365G>A has been reported in the literature in the heterozygous state in a Chinese individual affected with Hemophagocytic Lymphohistiocytosis with no second variant reported (Chen_2018). This does not provide unequivocal conclusions about association of the variant with Familial Hemophagocytic Lymphohistiocytosis. To our knowledge, there are no publications with experimental evidence demonstrating an impact on protein function. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Two laboratories classified the variant as benign and one as VUS. Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV003918052	SCV004733716	likely benign	STXBP2-related disorder	2022-03-11	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).