ClinVar Miner

Submissions for variant NM_006949.4(STXBP2):c.497C>T (p.Thr166Met)

gnomAD frequency: 0.00031  dbSNP: rs181216956
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000502479 SCV000597325 likely benign not specified 2015-11-12 criteria provided, single submitter clinical testing
Invitae RCV000960504 SCV001107483 benign Familial hemophagocytic lymphohistiocytosis 5 2024-02-01 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000960504 SCV001288652 benign Familial hemophagocytic lymphohistiocytosis 5 2017-04-27 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000502479 SCV002103833 benign not specified 2023-07-28 criteria provided, single submitter clinical testing Variant summary: STXBP2 c.497C>T (p.Thr166Met) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0011 in 157034 control chromosomes, predominantly at a frequency of 0.016 within the East Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 7-fold of the estimated maximal expected 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 East Asian origin. c.497C>T has been reported in the literature in East Asian individuals affected with Familial Hemophagocytic Lymphohistiocytosis (e.g. Chen_2016, Miao_2019, Zhang_2019, Zhang_2020, Xu_2022), however most reported individuals carried the variant in monoallelic form, and some authors also noted that the frequency of the variant was similar to that found in ethinically matched controls (e.g. Miao_2019). These reports do not provide unequivocal conclusions about association of the variant with Familial Hemophagocytic Lymphohistiocytosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27209435, 30899265, 31388699, 32375849, 35296096). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.

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