Submissions for variant NM_000444.6(PHEX):c.2237G>T (p.Cys746Phe)

dbSNP: rs1057517799

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413405	SCV000490718	likely pathogenic	not provided	2016-04-08	criteria provided, single submitter	clinical testing	The C746F variant has not beenpublished as a pathogenic variant, nor has it been reported as a benign variant to our knowledge.C746F was not observed in approximately 6500 individuals of European and African Americanancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant inthese populations. The C746F variant is a non- conservative amino acid substitution, which is likelyto impact secondary protein structure as these residues differ in polarity, charge, size and/or otherproperties. This substitution occurs at a highly conserved cysteine residue in the extracellular domain,and in silico analysis predicts this variant is probably damaging to the protein structure/function.Missense variants in the same (C746Y/W) and nearby residues (W749R/S) have been reported in theHuman Gene Mutation Database in association with hypophosphataemic rickets (Stenson et al.,2014), supporting the functional importance of this region of the protein. Therefore, this variant islikely pathogenic; however, the possibility that it is benign cannot be excluded.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000413405	SCV003257804	likely pathogenic	not provided	2023-01-10	criteria provided, single submitter	clinical testing	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.Cys746 amino acid residue in PHEX. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23813354). 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: 372465). This missense change has been observed in individual(s) with PHEX-related conditions (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 746 of the PHEX protein (p.Cys746Phe).
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV004545879	SCV004231756	likely pathogenic	Familial X-linked hypophosphatemic vitamin D refractory rickets	2024-01-12	criteria provided, single submitter	clinical testing