Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001052236 | SCV001216437 | pathogenic | Autosomal recessive polycystic kidney disease | 2023-11-02 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 2016 of the PKHD1 protein (p.Ser2016Cys). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individual(s) with autosomal recessive polycystic kidney disease (PMID: 15698423; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 848469). 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 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, |
RCV001779110 | SCV002015028 | uncertain significance | not specified | 2021-10-22 | criteria provided, single submitter | clinical testing | Variant summary: PKHD1 c.6046A>T (p.Ser2016Cys) results in a non-conservative amino acid change located in the G8 domain (IPR019316) of the encoded protein sequence. Four 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 251372 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6046A>T has been reported in the literature as a compound heterozygous genotype in at-least one individual affected with Polycystic Kidney And Hepatic Disease and has been subsequently cited by others (example, Bergmann_2005, Burgmaier_2021). 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. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic citing an overlapping evidence utilized in the context of this evaluation and an internal observation (genotype and/or clinical characteristics not specified). Based on the evidence outlined above, until additional genotyped patients supported by a functional evidence is identified, the variant was classified as uncertain significance. |
| Prevention |
RCV003396673 | SCV004110822 | uncertain significance | PKHD1-related disorder | 2023-03-27 | criteria provided, single submitter | clinical testing | The PKHD1 c.6046A>T variant is predicted to result in the amino acid substitution p.Ser2016Cys. This variant was reported in an individual with polycystic kidney disease (Table 1, Bergmann et al 2005. PubMed ID: 15698423). This variant is reported in 0.0026% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/6-51798983-T-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |
| Baylor Genetics | RCV003473648 | SCV004202215 | likely pathogenic | Polycystic kidney disease 4 | 2023-10-27 | criteria provided, single submitter | clinical testing |