Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001378985 | SCV001576699 | likely pathogenic | not provided | 2020-03-16 | 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. 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 has been observed in individuals with hypophosphatemia (PMID: 27840894, Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 275 of the PHEX protein (p.Leu275Pro). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and proline. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003235569 | SCV003934514 | likely pathogenic | Familial X-linked hypophosphatemic vitamin D refractory rickets | 2023-05-12 | criteria provided, single submitter | clinical testing | Variant summary: PHEX c.824T>C (p.Leu275Pro) results in a non-conservative amino acid change located in the Peptidase M13, N-terminal domain (IPR008753) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183136 control chromosomes (gnomAD). c.824T>C has been reported in the literature in individuals affected with X-Linked Hypophosphatemic Rickets and this variant co-segregated with the disease (Li_2016). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27840894, 34141703, 34806794, 30682568). One ClinVar submitter (evaluation after 2014) cites this variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |