Submissions for variant NM_002547.3(OPHN1):c.1202-1G>A

dbSNP: rs2147456067

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Kids Neuroscience Centre, Sydney Children's Hospitals Network	RCV001726524	SCV001571536	likely pathogenic	X-linked intellectual disability-cerebellar hypoplasia syndrome		criteria provided, single submitter	clinical testing	The c.1202-1G>A variant induces three abnormal splicing events: (1) Use of a cryptic 3’ splice site (r.1202del). This event causes a frameshift encoding 19 missense amino acids and a premature termination codon (p.Ile402Serfs*20). These transcripts are predicted to be targeted by nonsensemediated decay (NMD). Any mis-spliced transcripts that escape NMD encode OPHN1 protein lacking 401 amino acids from the C-terminus, including 162 residues from the Rho-GTPase-activating protein domain, (2) Exon 15 skipping (r.1202_1276del). This in-frame deletion removes 15 amino acids from the Rho-GTPaseactivating protein domain of OPHN1 (p.Gly401_Phe425del), (3) Exons 13, 14 and 15 skipping (r.1105_1276del). This event causes a frameshift encoding 22 missense amino acids and a premature termination codon (p.Tyr370Leufs*23). These transcripts are predicted to be targeted by NMD. Any mis-spliced transcripts that escape NMD encode OPHN1 protein lacking 433 amino acids from the Cterminus, including 183 residues from the Rho-GTPase activating protein domain.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001726524	SCV002768611	likely pathogenic	X-linked intellectual disability-cerebellar hypoplasia syndrome	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Likely Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with OPHN1 -related neurodevelopmental syndrome. (I) 0109 - This gene is associated with X-linked recessive disease. (I) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. Analysis of patient mRNA demonstrated that this variant causes aberrant splicing with three different effects. These include the use of a cryptic 3' splice site, exon 15 skipping and exon 13-15 skipping, resulting in the protein consequences p.(Ile402Serfs*20), p.(Tyr370Leufs*23) and p.(Gly401_Phe425del)) (Splicing Diagnostics, Kids Neuroscience Centre). (SP) 0253 - This variant is hemizygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0705 - No comparable splice variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign