ClinVar Miner

Submissions for variant NM_000444.6(PHEX):c.1368G>C (p.Trp456Cys) (rs886043680)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000413461 SCV000341459 uncertain significance not provided 2016-06-01 criteria provided, single submitter clinical testing
GeneDx RCV000413461 SCV000491263 likely pathogenic not provided 2016-07-19 criteria provided, single submitter clinical testing This variant has been previously published in association with X-linked hypophosphatemic rickets (Filisetti et al., 1999; Quinlan et al., 2012) with limited data to fully support pathogenicity. The W456C variant 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 W456C 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 in silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant in a nearby residue (L450P) has also 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. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae RCV000413461 SCV001396645 pathogenic not provided 2020-10-01 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with cysteine at codon 456 of the PHEX protein (p.Trp456Cys). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with hypophosphatemia in a family and has been observed in several additional unrelated patients (PMID: 22101457, 29460029, 10439971, Invitae). ClinVar contains an entry for this variant (Variation ID: 287635). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Trp456 amino acid residue in PHEX. Other variant(s) that disrupt this residue have been observed in individuals with PHEX-related conditions (PMID: 29460029), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

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