PHEX was first reported in relation to X-linked dominant hypophosphatemic rickets in 1995 (The HYP Consortium, PMID: 7550339). 14 variants (missense, nonsense, frameshift, splicing) that have been reported in at least 15 probands in 5 publications are included in this curation (PMIDs: 19219621, 29460029, 30682568, 32253725, 33639975). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss-of-function. This gene-disease relationship is also supported by a mouse model (PMIDs: 188049, 1569185). Mutant mice show delayed growth, hypophosphatemia. and skeletal anomalies. Supplementation with phosphate in the mutant suppressed the phenotype. In summary, there is definitive evidence supporting the relationship between PHEX and X-linked dominant hypophosphatemia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Tubulopathy GCEP on the meeting date 05/15/2025 (SOP Version 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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