Submissions for variant NM_006949.4(STXBP2):c.247-2A>C

dbSNP: rs921624651

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001063093	SCV001227927	likely pathogenic	Familial hemophagocytic lymphohistiocytosis 5	2023-11-14	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 4 of the STXBP2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in STXBP2 are known to be pathogenic (PMID: 19804848, 22451424). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of hemophagocytic lymphohistiocytosis (Invitae). ClinVar contains an entry for this variant (Variation ID: 857426). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002307673	SCV002600365	likely pathogenic	Familial hemophagocytic lymphohistiocytosis	2022-10-09	criteria provided, single submitter	clinical testing	Variant summary: STXBP2 c.247-2A>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a canonical 3' acceptor site. Three predict the variant creates a cryptic 3' acceptor site and one predicts the variant strengthens a cryptic 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251440 control chromosomes (gnomAD). To our knowledge, no occurrence of c.247-2A>C in individuals affected with Familial Hemophagocytic Lymphohistiocytosis and no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submitter has assessed the variant since 2014: the variant was classified as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.