Submissions for variant NM_014467.3(SRPX2):c.961+1G>A

gnomAD frequency: 0.00002  dbSNP: rs1303998333

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001345689	SCV001539826	uncertain significance	Rolandic epilepsy, intellectual disability, and speech dyspraxia, X-linked	2020-03-17	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in SRPX2 cause disease. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individual(s) with autism spectrum disorder (PMID: 23352160). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 8 of the SRPX2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001824954	SCV002074375	uncertain significance	not specified	2022-01-20	criteria provided, single submitter	clinical testing	Variant summary: SRPX2 c.961+1G>A alters a conserved nucleotide 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: Four predict the variant abolishes the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 174130 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. Although c.961+1G>A has been reported in an individual with autism (example, Lim_2013), to our knowledge, no occurrence of c.961+1G>A in individuals affected with Rolandic Epilepsy With Mental Retardation And Speech Dyspraxia, X-Linked and no experimental evidence demonstrating its impact on protein function have been reported. Subsequently the role of SRPX2 in the phenotype of Rolandic epilepsy has been disputed (Reinthaler_2014) while an association with autism is not fully established in the literature. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 classified the variant as uncertain significance citing overlapping evidence utilized in the context of this evalution. Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003416242	SCV004114937	uncertain significance	SRPX2-related disorder	2023-01-18	criteria provided, single submitter	clinical testing	The SRPX2 c.961+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported in an individual with autism spectrum disorder (Table S7 - Lim et al. 2013. PubMed ID: 23352160). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.