ClinVar Miner

Submissions for variant NM_033419.5(PGAP3):c.402dup (p.Met135fs)

dbSNP: rs869312812
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV000210252 SCV001132547 pathogenic Hyperphosphatasia with intellectual disability syndrome 4 2018-11-15 criteria provided, single submitter research The homozygous p.Met135HisfsTer28 variant in PGAP3 was identified by our study in two siblings with Hyperphosphatasia with Mental Retardation syndrome. This variant has been reported in the literature in the case of one compound heterozygous affected proband who was also found to have the 558-10C>T likely pathogenic variant (Knaus et al. 2016, PMID: 27120253). It has also been reported in 9 homozygous affected individuals across 7 consanguinous families and 2 non-consanguinous families (Abdel-Hamid et al. 2018, PMID: 28390064). This variant was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 135 and leads to a premature termination codon 28 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the PGAP3 gene is an established disease mechanism in Hyperphosphatasia with Mental Retardation Syndrome, and this is a loss of function variant. In summary, the variant p.Met135HisfsTer28 is pathogenic.
GeneDx RCV001008867 SCV001168672 pathogenic not provided 2021-03-02 criteria provided, single submitter clinical testing Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 27120253, 29531774, 28390064, 29310717)
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin RCV000210252 SCV000266254 pathogenic Hyperphosphatasia with intellectual disability syndrome 4 2016-03-01 no assertion criteria provided research Disease causing variant in homozygous or compound heterozygous state

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