Submissions for variant NM_006949.4(STXBP2):c.568C>T (p.Arg190Cys)

gnomAD frequency: 0.00041  dbSNP: rs370053399

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000477888	SCV000769113	likely benign	Familial hemophagocytic lymphohistiocytosis 5	2024-01-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000658815	SCV000780611	uncertain significance	not provided	2017-12-01	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000658815	SCV000861500	uncertain significance	not provided	2018-06-11	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000477888	SCV000899004	uncertain significance	Familial hemophagocytic lymphohistiocytosis 5	2021-03-30	criteria provided, single submitter	clinical testing	STXBP2 NM_006949 exon 7 p.Arg190Cys (c.568C>T): This variant has been reported in the literature in 1 individual with hemophagocytic lymphohistiocytosis as a double heterozygote (Zhang 2014 PMID:24916509). This variant is present in 0.2% (21/8488) of Ashkenazi Jewish alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs370053399). This variant is present in ClinVar (Variation ID:404841). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Illumina Laboratory Services, Illumina	RCV000477888	SCV001288653	uncertain significance	Familial hemophagocytic lymphohistiocytosis 5	2017-05-26	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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004526685	SCV005039758	uncertain significance	not specified	2024-03-19	criteria provided, single submitter	clinical testing	Variant summary: STXBP2 c.568C>T (p.Arg190Cys) 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 0.00048 in 157426 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in STXBP2 causing Familial Hemophagocytic Lymphohistiocytosis (0.00048 vs 0.0022), allowing no conclusion about variant significance. c.568C>T has been reported in the literature in heterozygous individuals affected with Familial Hemophagocytic Lymphohistiocytosis (e.g. Zhang_2014, Benavides_2020, Vinas-Gimenez_2021), and some were reported to also have variants in other genes. These reports do not provide unequivocal conclusions about association of the variant with Familial Hemophagocytic Lymphohistiocytosis. Publications report experimental evidence evaluating an impact on protein function, finding that the variant results in diminished degranulation and target cell apoptosis (Benavides_2020, Vinas-Gimenez_2021). However, this does not allow convincing conclusions about the variant effect. The following publications have been ascertained in the context of this evaluation (PMID: 24916509, 33162974, 34630398, 31286990, 37477760). ClinVar contains an entry for this variant (Variation ID: 417965). Based on the evidence outlined above, the variant was classified as uncertain significance.
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000477888	SCV000536933	uncertain significance	Familial hemophagocytic lymphohistiocytosis 5	2016-05-28	no assertion criteria provided	research
GeneReviews	RCV000477888	SCV001976574	not provided	Familial hemophagocytic lymphohistiocytosis 5		no assertion provided	literature only	Dominant-negative variant assoc w/fHLH in 1 infant [Benavides et al 2020]