Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003155817 | SCV003844942 | likely pathogenic | Familial X-linked hypophosphatemic vitamin D refractory rickets | 2023-02-03 | criteria provided, single submitter | clinical testing | Variant summary: The variant identified by MLPA or other technology involves the duplication of exons 13-15 in the PHEX gene. A presumed nomenclature of c.(1404+1_1405-1)_(1645+1_1646-1)dup has been designated for the purposes of this classification. It has been assumed that this is a tandem duplication in direct orientation (Richardson_GIM_2018, Newman_AJHG_2015). Although exact breakpoints of this duplication are not known, it is expected to result in a frameshift in the PHEX gene. The variant was absent in 15814 control chromosomes in gnomAD database (structural variants dataset). Exons13-15dup has been reported in the literature in several individuals affected with X-Linked Hypophosphatemic Rickets (Sarafrazi_2022, Rush_2022, McCrystal Dahir_2022). In at least one patient this variant was found in isolation (Rush_2022), however in all other patients the variant was found together with c.*231A>G, and in all of them occurring in cis (i.e. as a complex allele), where phasing information was available. The co-occurring 3'-UTR variant is located three base pairs upstream of the polyadenylation signal of PHEX, thus it remains unclear whether it is just a marker for this pathogenic duplication, or can be also detrimental in isolation. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |