Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000478030 | SCV000568747 | likely pathogenic | not provided | 2017-02-21 | criteria provided, single submitter | clinical testing | The G553E variant has been published previously in association with X-linked hypophosphatemic rickets (Ruppe et al., 2011). The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). G553E 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. Missense variants in nearby residues (I548T, R549P, L555P, P558R) 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. |
Invitae | RCV000478030 | SCV003444631 | pathogenic | not provided | 2023-10-29 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 553 of the PHEX protein (p.Gly553Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypophosphatemic rickets (PMID: 21050253, 32329911). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 420130). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PHEX function (PMID: 32329911). For these reasons, this variant has been classified as Pathogenic. |