Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003236330 | SCV003934194 | uncertain significance | not specified | 2023-05-02 | criteria provided, single submitter | clinical testing | Variant summary: PKHD1 c.7205G>A (p.Gly2402Asp) results in a non-conservative amino acid change located in the Right handed beta helix domain (IPR039448) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 249276 control chromosomes. c.7205G>A has been reported in the literature in individuals affected with Polycystic Kidney And Hepatic Disease (Xu_2021). These data indicate that the variant may 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: 34977057). 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 | RCV003611635 | SCV004548339 | pathogenic | Autosomal recessive polycystic kidney disease | 2023-10-18 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 2402 of the PKHD1 protein (p.Gly2402Asp). This variant is present in population databases (no rsID available, gnomAD 0.02%). This missense change has been observed in individual(s) with polycystic kidney disease (PMID: 34977057). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2506099). 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. For these reasons, this variant has been classified as Pathogenic. |