Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001863170 | SCV002243953 | pathogenic | Autosomal recessive polycystic kidney disease | 2023-03-28 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 997307). This missense change has been observed in individual(s) with PKHD1-related conditions (PMID: 22882926, 31328266, 31813136, 34032358). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1979 of the PKHD1 protein (p.Gly1979Arg). |
| Fulgent Genetics, |
RCV002504426 | SCV002808738 | likely pathogenic | Polycystic kidney disease 4 | 2022-04-13 | criteria provided, single submitter | clinical testing | |
| Baylor Genetics | RCV002504426 | SCV004204710 | likely pathogenic | Polycystic kidney disease 4 | 2023-03-18 | criteria provided, single submitter | clinical testing | |
| Department of Pathology and Laboratory Medicine, |
RCV001292352 | SCV001480707 | likely pathogenic | Polycystic kidney disease | no assertion criteria provided | clinical testing | The PKHD1 p.Gly1979Arg variant was identified in the literature in one study in a patient with autosomal recessive polycystic kidney disease (Zhang 2012). The variant was not identified in the following databases: dbSNP, ClinVar, Clinvitae, LOVD 3.0, or the RWTH AAachen University ARPKD database. The variant was not identified in the control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Gly1979Arg residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic. |