ClinVar Miner

Submissions for variant NM_000444.6(PHEX):c.1601C>T (p.Pro534Leu) (rs886041363)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000260839 SCV000329878 pathogenic not provided 2018-11-09 criteria provided, single submitter clinical testing The P534L missense variant in the PHEX gene has been reported previously in association with X-linked hypophosphatemic rickets, including one instance of de novo inheritance (Filisetti et al., 1999; Holm et al., 2001; Yavropoulou et al., 2010; Mumm et al., 2015). The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. P534L is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function.
Institute of Human Genetics, Klinikum rechts der Isar RCV000505461 SCV000599609 pathogenic Familial X-linked hypophosphatemic vitamin D refractory rickets 2013-11-19 criteria provided, single submitter clinical testing
Mendelics RCV000505461 SCV001141539 pathogenic Familial X-linked hypophosphatemic vitamin D refractory rickets 2019-05-28 criteria provided, single submitter clinical testing
Invitae RCV000260839 SCV001206281 pathogenic not provided 2019-12-11 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 534 of the PHEX protein (p.Pro534Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in multiple individuals and families affected with PHEX-related conditions (PMID: 29505567, 18162710, 19219621, 29460029, 22261628, 9097956). ClinVar contains an entry for this variant (Variation ID: 280076). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.

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