Submissions for variant NM_000444.6(PHEX):c.2079C>G (p.Cys693Trp)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000478394	SCV000573971	likely pathogenic	not provided	2017-03-06	criteria provided, single submitter	clinical testing	To our knowledge, the C693W variant has not been published as a pathogenic variant, nor has it been reported as a benign variant. The C693W variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). It is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other 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. Additionally, missense variants at the same (C693Y/F) and in a nearby residue (A689D) have been reported in the Human Gene Mutation Database in association with hypophosphatemic rickets (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Mendelics	RCV002248710	SCV002517358	likely pathogenic	Familial X-linked hypophosphatemic vitamin D refractory rickets	2022-05-04	criteria provided, single submitter	clinical testing
Invitae	RCV000478394	SCV004429387	likely pathogenic	not provided	2023-01-07	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with X-linked hypophosphatemia (Invitae). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Cys693 amino acid residue in PHEX. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10737991, 30682568; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PHEX protein function. ClinVar contains an entry for this variant (Variation ID: 424185). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 693 of the PHEX protein (p.Cys693Trp).

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