Submissions for variant NM_001032221.6(STXBP1):c.37+2dup

dbSNP: rs1838431452

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001089985	SCV001244977	likely pathogenic	Developmental and epileptic encephalopathy, 4	2018-06-09	criteria provided, single submitter	clinical testing	A heterozygous duplication variant, NM_003165.3(STXBP1):c.37+2dupT, has been identified in intron 1 of 19 of the STXBP1 gene. This variant alters the conserved splice donor recognition site of intron 1 and is predicted to result in loss of protein function either through truncation or nonsense-mediated decay. Further tesing (RNA studies) is required to confirm splicing is affected. The variant is absent in population databases (gnomAD, dbSNP, 1000G), and has not been previously reported in clinical cases. Several variants in the same splice recognition site have also been shown to cause epileptic encephalopathy (Trump et al., 2016; ClinVar). Analysis of parental samples indicated this variant to be de novo. Based on the information available at the time of curation, this variant has been classified as LIKELY PATHOGENIC.
Institute of Molecular Medicine and Oncology, Chongqing Medical University	RCV001089985	SCV001431535	pathogenic	Developmental and epileptic encephalopathy, 4	2020-08-06	criteria provided, single submitter	clinical testing	We observed a young female patient with a de novo variant NM_003165.6 c.37+2dup of STXBP1.Her clinical symptoms overlapped with symptoms of STXBP1-E, including seizures, intellectual impairment, and dyskinesia. The variation belonged to a donor site mutation at the splice site, which resulted in haploinsufficiency. Unlike the common single nucleotide variant of STXBP1, splicing mutations can produce truncated proteins and even mRNA degradation. The protein cannot be adequately translated, which has a severe impact on brain development. We believe that this discovery provided additional information about the cause of STXBP1-E. Given that this case is an unreported variation, future genetic counseling for such patients and the exploration of the underlying mechanisms of pathogenesis and subsequent treatment will be critical issues.