ClinVar Miner

Submissions for variant NM_033419.5(PGAP3):c.694+1G>A

gnomAD frequency: 0.00001  dbSNP: rs144574243
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000413162 SCV000491878 pathogenic not provided 2016-11-25 criteria provided, single submitter clinical testing The c.694+1G>A variant in the PGAP3 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This splice site variant destroys the canonical splice donor site in intron 6. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.694+1G>A variant was not observed at any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.694+1G>A as a pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp RCV000413162 SCV002952122 pathogenic not provided 2024-09-06 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 6 of the PGAP3 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 PGAP3 are known to be pathogenic (PMID: 2443911, 27120253). This variant is present in population databases (rs144574243, gnomAD 0.003%). Disruption of this splice site has been observed in individual(s) with clinical features of PGAP3-related conditions (internal data). 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: 373293). 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.
Revvity Omics, Revvity RCV003137996 SCV003822841 pathogenic Hyperphosphatasia with intellectual disability syndrome 4 2022-06-24 criteria provided, single submitter clinical testing

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