Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Counsyl | RCV000673683 | SCV000798913 | uncertain significance | Autosomal recessive polycystic kidney disease | 2018-03-28 | criteria provided, single submitter | clinical testing | |
| Blueprint Genetics | RCV000788834 | SCV000928094 | likely pathogenic | not provided | 2018-12-03 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV000673683 | SCV003508225 | pathogenic | Autosomal recessive polycystic kidney disease | 2024-11-27 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 3353 of the PKHD1 protein (p.Leu3353Arg). This variant is present in population databases (rs777377414, gnomAD 0.02%). This missense change has been observed in individual(s) with polycystic kidney disease (PMID: 28578020). 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: 557530). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PKHD1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003330894 | SCV004039102 | uncertain significance | not specified | 2023-08-11 | criteria provided, single submitter | clinical testing | Variant summary: PKHD1 c.10058T>G (p.Leu3353Arg) results in a non-conservative amino acid change in 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 1.2e-05 in 251236 control chromosomes. c.10058T>G has been reported in the literature in compound heterozygosity with a second pathogenic variant (c.2341C>T; p.R781X) in two fetuses affected with bilateral kidney enlargement (e.g. Fang_2017). It has also been reported in heterozygosity and compound heterozygosity with variants of uncertain significance in other individuals with Polycystic Kidney And Hepatic Disease (e.g. Fang_2017, Yu_2022, Fu_2022), but the effect of the alterations in these individuals is less clear. 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: 28578020, 35778421, 36307859). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One classified the variant as pathogenic, one classified the variant as likely pathogenic, and one classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |
| Baylor Genetics | RCV003459642 | SCV004204572 | likely pathogenic | Polycystic kidney disease 4 | 2023-08-23 | criteria provided, single submitter | clinical testing |