Submissions for variant NM_020638.3(FGF23):c.535C>T (p.Arg179Trp)

dbSNP: rs28937882

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000424624	SCV000521161	likely pathogenic	not provided	2015-11-20	criteria provided, single submitter	clinical testing	The R179W variant that is likely pathogenic has been published previously in association with autosomal dominant hypophosphateaemic rickets (Imel et al., 2011; ADHR consortium, 2000). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R179W variant 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 is cleaved by proprotein convertases (Komaba et al., 2012). In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants at the same codon (R179Q) and in nearby residues (R176W/Q) have been reported in the Human Gene Mutation Database in association with autosomal dominant hypophosphatemic rickets (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München	RCV000005329	SCV000608353	pathogenic	Autosomal dominant hypophosphatemic rickets	2013-12-05	criteria provided, single submitter	clinical testing
Invitae	RCV000424624	SCV002245443	pathogenic	not provided	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 179 of the FGF23 protein (p.Arg179Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant hypophosphatemic rickets (PMID: 11062477, 21880793, 31486862, 32415663). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5026). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FGF23 protein function. This variant disrupts the p.Arg179 amino acid residue in FGF23. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11062477, 21880793, 26186302). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000005329	SCV000025507	pathogenic	Autosomal dominant hypophosphatemic rickets	2000-11-01	no assertion criteria provided	literature only