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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