Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002266158 | SCV002547683 | uncertain significance | not specified | 2022-05-20 | criteria provided, single submitter | clinical testing | Variant summary: PKHD1 c.4165C>A (p.Pro1389Thr) results in a non-conservative amino acid change located in the IPT domain (IPR002909) 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 251380 control chromosomes. c.4165C>A has been reported in the literature as a compound heterozygous genotype in one individual with features of Autosomal recessive polycystic kidney disease (Bullich_2018) and as a non-informative genotype (exact genotype/zygosity not clearly specified) in another individual from a cohort of pedigrees with congenital hepatic fibrosis and/or Carolis disease (example, Rossetti_2003) with subsequent citations by others (example, Bergmann_2005, Sharp_2005). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |
| Invitae | RCV003502614 | SCV004293757 | likely pathogenic | Autosomal recessive polycystic kidney disease | 2023-04-23 | criteria provided, single submitter | clinical testing | 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 PKHD1 protein function. 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. ClinVar contains an entry for this variant (Variation ID: 1696015). This missense change has been observed in individual(s) with polycystic kidney disease (PMID: 29801666). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1389 of the PKHD1 protein (p.Pro1389Thr). |