Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001069479 | SCV001234646 | pathogenic | Autosomal recessive polycystic kidney disease | 2023-12-31 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1944 of the PKHD1 protein (p.Asp1944Asn). This variant is present in population databases (rs774290802, gnomAD 0.007%). This missense change has been observed in individual(s) with polycystic kidney disease (PMID: 26673778, 27225849). 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: 862704). 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. |
| Fulgent Genetics, |
RCV002497474 | SCV002811084 | likely pathogenic | Polycystic kidney disease 4 | 2022-05-16 | criteria provided, single submitter | clinical testing | |
| Baylor Genetics | RCV002497474 | SCV004204587 | pathogenic | Polycystic kidney disease 4 | 2023-08-09 | criteria provided, single submitter | clinical testing | |
| Sydney Genome Diagnostics, |
RCV001069479 | SCV001449396 | uncertain significance | Autosomal recessive polycystic kidney disease | 2018-04-17 | no assertion criteria provided | clinical testing | c.5830G>A (p.Asp1944Asn) has been listed in the ExAC database (http://exac.broadinstitute.org/) with a very low allele frequency 0.0016% (2 out of 121,244 alleles). To our knowledge, this variant has not been previously reported in the literature or any variant databases associated with disease. p.Asp1944 is a moderately conserved amino acid (up to 15 species). In silico analysis of pathogenicity (through Alamut Visual v2.8) is inconclusive regarding this change; SIFT predicts this variant to be tolerated whereas PolyPhen2 & Mutation Taster predict that this variant is likely to be pathogenic. This variant is considered to be a variant of uncertain clinical significance (VOUS) according to the ACMG guidelines. |
| Genetic Services Laboratory, |
RCV003151279 | SCV003839873 | likely pathogenic | not provided | 2022-06-02 | no assertion criteria provided | clinical testing | DNA sequence analysis of the PKHD1 gene demonstrated a sequence change, c.5830G>A, in exon 36 that results in an amino acid change, p.Asp1944Asn. The p.Asp1944Asn change affects a highly conserved amino acid residue located in a domain of the PKHD1 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Asp1944Asn substitution. This sequence change has been described in the literature in individuals with PKHD1 polycystic kidney disease (PMID: 26673778, 27225849). This sequence change has been described in the gnomAD database with a frequency of 0.012% in the African/African American subpopulation (dbSNP rs774290802). Based on these evidences, this sequence change is classified as likely pathogenic, however functional studies have not been performed to prove this conclusively. |