Submissions for variant NM_000444.6(PHEX):c.914T>G (p.Leu305Arg)

dbSNP: rs1064796929

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000481234	SCV000574158	uncertain significance	not provided	2017-03-13	criteria provided, single submitter	clinical testing	To our knowledge, the L305R variant has not been published as a pathogenic variant, nor has it been reported as a benign variant. The L305R variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). It 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, a different missense change at the same codon (L305P) has been reported in a patient with hypophosphatemic rickets (Raeder et al., 2008). However, no other missense variants in nearby residues have been reported in the Human Gene Mutation Database (Stenson et al., 2014). In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000481234	SCV004502662	likely pathogenic	not provided	2023-03-30	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 missense change has been observed in individual(s) with hypophosphatemic rickets (Invitae). ClinVar contains an entry for this variant (Variation ID: 424357). 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. This variant disrupts the p.Leu305 amino acid residue in PHEX. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18775977). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 305 of the PHEX protein (p.Leu305Arg).