Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Counsyl | RCV000670644 | SCV000795524 | uncertain significance | Autosomal recessive polycystic kidney disease | 2017-11-08 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001527048 | SCV001737880 | uncertain significance | not specified | 2021-06-05 | criteria provided, single submitter | clinical testing | Variant summary: PKHD1 c.6097A>G (p.Arg2033Gly) results in a non-conservative amino acid change located in the G8 domain (IPR019316) of 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 251288 control chromosomes. c.6097A>G has been reported in the literature in individuals affected with Polycystic Kidney And Hepatic Disease (example, Adeya_2006, Gunay-Aygun_2010, LingChen_2019). One of these reports described this variant in a compound heterozygous genotype with p.Q3392X in a family with two sibs, one of whom was reportedly unaffected with diffuse low attenuation in the liver consistent with fatty infiltration while the other had congenital hepatic fibrosis and renal enlargement but no evidence of kidney dysfunction or hypersplenism (Adeva_2006). The authors reported this as a "mild mutation" in patients with a predominant biliary phenotype. Another report described the variant in a compound heterozygous genotype with p.Ile2957Thr in two non-perinatal onset cases from a family (Gunay-Aygun_2010). Finally, the third ascertained report in the context of this evaluation describes this variant in compound heterozygosity with p.Arg3772Ter in a patient with polycystic liver/kidney disease who underwent an NGS panel for 42 known disease causing genes associated with jaundice or cholestasis and 10 pathway related genes (Ling Chen_2019). These data indicate that the variant maybe associated with disease. 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 uncertain significance citing overlapping evidence cited here. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic until additional clinical reports and functional evidence are identified. |
| Invitae | RCV000670644 | SCV002206031 | pathogenic | Autosomal recessive polycystic kidney disease | 2024-01-24 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 2033 of the PKHD1 protein (p.Arg2033Gly). This variant is present in population databases (rs369626030, gnomAD 0.01%). This missense change has been observed in individuals with polycystic kidney disease (PMID: 16523049, 20413436, 30366773). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 554925). 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. |
| Baylor Genetics | RCV003472125 | SCV004202271 | pathogenic | Polycystic kidney disease 4 | 2023-09-28 | criteria provided, single submitter | clinical testing |