rs875989883
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong
The NM_000444.6(PHEX):c.1735G>A(p.Gly579Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G579V) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000444.6 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 24
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1072214Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0AN XY: 342346
GnomAD4 genome Cov.: 24
ClinVar
Submissions by phenotype
Familial X-linked hypophosphatemic vitamin D refractory rickets Pathogenic:5
- -
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). -
The identified PHEX mutation is the likely genetic cause for the hypophosphatemic rickets observed in the patient. -
- -
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000226119,VCV000438542, PS1_S). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M).Different missense changes at the same codon (p.Gly579Val, p.Gly579Glu) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000372777,VCV000378359, PMID:9097956, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.931, 3CNET: 0.997, PP3_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
not provided Pathogenic:2
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 579 of the PHEX protein (p.Gly579Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypophosphatemic rickets (PMID: 9097956, 9199930, 18625346, 29858904). ClinVar contains an entry for this variant (Variation ID: 226119). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 11468271). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
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). -
Vitamin D-dependent rickets, type 2 Pathogenic:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at