Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| 3billion | RCV003152985 | SCV003841616 | likely pathogenic | Polycystic kidney disease 4 | 2023-02-23 | criteria provided, single submitter | clinical testing | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.69; 3Cnet: 0.94). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with PKHD1-related disorder (PMID: 32901917). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (3billion dataset). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. |
| Baylor Genetics | RCV003152985 | SCV004202251 | pathogenic | Polycystic kidney disease 4 | 2024-01-17 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV003611631 | SCV004516484 | likely pathogenic | Autosomal recessive polycystic kidney disease | 2024-01-08 | criteria provided, single submitter | clinical testing | This sequence change replaces tryptophan, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 1725 of the PKHD1 protein (p.Trp1725Ser). This variant is present in population databases (rs761046498, gnomAD 0.01%). This missense change has been observed in individual(s) with polycystic kidney disease (PMID: 32901917, 34536170). 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: 2444187). 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%. 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. |