ClinVar Miner

Submissions for variant NM_000444.6(PHEX):c.1735G>A (p.Gly579Arg) (rs875989883)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center of Genomic medicine, Geneva,University Hospital of Geneva RCV000211521 SCV000268522 likely pathogenic Familial X-linked hypophosphatemic vitamin D refractory rickets 2016-04-05 criteria provided, single submitter clinical testing The identified PHEX mutation is the likely genetic cause for the hypophosphatemic rickets observed in the patient.
GeneDx RCV000396672 SCV000329463 pathogenic not provided 2018-09-19 criteria provided, single submitter clinical testing The G579R missense variant in the PHEX gene has been reported previously as de novo and in association with X-linked hypophosphatemic rickets (Rowe et al., 1997; Durmaz et al., 2013; Radlovic et al., 2014). The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). G579R 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. In addition, another nucelotide change at the same codon (c.1735 G>C) also leading to the G579R missense change, a missense variant in at the same residue (G579V), and missense variants in nearby residues (H580P, F582S, H584P) have all been reported in the Human Gene Mutation Database in association with PHEX-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Furthermore, functional studies of the G579R variant have shown that it results in incomplete glycosylation of the protein leading to failed expression at the plasma membrane and degradation within the endoplasmic reticulum (Sabbagh et al., 2001; Sabbagh et al., 2003).
Institute of Human Genetics, Klinikum rechts der Isar RCV000211521 SCV000599652 pathogenic Familial X-linked hypophosphatemic vitamin D refractory rickets 2013-10-28 criteria provided, single submitter clinical testing
SIB Swiss Institute of Bioinformatics RCV000211521 SCV000803531 pathogenic Familial X-linked hypophosphatemic vitamin D refractory rickets 2018-05-31 criteria provided, single submitter curation This variant is interpreted as a Pathogenic, for Hypophosphatemic rickets, X-linked dominant, in X-linked Dominant manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => Recurrent mutation found in unrelated patients. (PMID:9199930). PS3 => Well-established functional studies show a deleterious effect (PMID:11468271,12727977). PM6 => Assumed de novo, but without confirmation of paternity and maternity (PMID:24684036).
Invitae RCV000396672 SCV001217754 pathogenic not provided 2019-12-24 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 579 of the PHEX protein (p.Gly579Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in many individuals affected with hypophosphatemic rickets (PMID: 9199930, 18625346, 29858904, 9097956). ClinVar contains an entry for this variant (Variation ID: 226119). This variant has been reported to affect PHEX protein function (PMID: 11468271). For these reasons, this variant has been classified as Pathogenic.
Department of Traditional Chinese Medicine,Fujian Provincial Hospital RCV000578203 SCV000680000 likely pathogenic Vitamin D-dependent rickets, type 2 2017-04-01 no assertion criteria provided research

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.