Submissions for variant NM_033419.5(PGAP3):c.558-10G>A

gnomAD frequency: 0.00009  dbSNP: rs200598755

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000493918	SCV000582668	pathogenic	not provided	2023-05-05	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect resulting in abnormal gene splicing (Knaus et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 27120253)
Baylor Genetics	RCV000210276	SCV001521055	likely pathogenic	Hyperphosphatasia with intellectual disability syndrome 4	2019-03-07	criteria provided, single submitter	clinical testing	This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	RCV000210276	SCV002574727	pathogenic	Hyperphosphatasia with intellectual disability syndrome 4	2022-06-30	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000210276	SCV002768319	likely pathogenic	Hyperphosphatasia with intellectual disability syndrome 4	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as likely pathogenic. The following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hyperphosphatasia with intellectual disability syndrome 4 (MIM#615716). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. Quantitative PCR demonstrated reduced transcript level and reduced splicing efficacy but didn't not show the protein impact (PMID: 27120253). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (21 heterozygotes, 0 homozygotes). (SP) 0508 - In silico predictions for abnormal splicing are conflicting. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported twice as likely pathogenic in ClinVar and also in two patients with hyperphosphatasia with intellectual disability syndrome (PMID: 27120253). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 0705 - No comparable splice site variants have previous evidence for pathogenicity. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Invitae	RCV000493918	SCV003441851	pathogenic	not provided	2023-12-09	criteria provided, single submitter	clinical testing	This sequence change falls in intron 5 of the PGAP3 gene. It does not directly change the encoded amino acid sequence of the PGAP3 protein. This variant is present in population databases (rs200598755, gnomAD 0.01%). This variant has been observed in individual(s) with PGAP3-congenital disorder of glycosylation (PMID: 27120253). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 224645). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	RCV000210276	SCV000266259	pathogenic	Hyperphosphatasia with intellectual disability syndrome 4	2016-03-01	no assertion criteria provided	research	Disease causing variant in homozygous or compound heterozygous state