ClinVar Miner

Submissions for variant NM_138694.4(PKHD1):c.8870T>C (p.Ile2957Thr) (rs760222236)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000390646 SCV000464050 pathogenic Autosomal recessive polycystic kidney disease 2017-04-27 criteria provided, single submitter clinical testing Across nine studies, the PKHD1 c.8870T>C (p.Ile2957Thr) missense variant is reported in a total of 23 patients, including 19 compound heterozygotes with autosomal recessive polycystic kidney disease (ARPKD), one compound heterozygote with Caroli's disease and congenital hepatic fibrosis with minimal kidney involvement, two ARPKD patients carrying three variants in the PKHD1 gene, and one heterozygote in whom a second variant was not identified (Onuchic et al. 2002; Ward et al. 2002; Bergmann et al. 2003; Rossetti et al. 2003; Sharp et al. 2005; Gunay-Aygun et al. 2010; Denamur et al. 2010; Brinkert et al. 2013; Melchionda et al. 2016). Additionally, the p.Ile2957Thr variant was found in a heterozygous state in three unaffected family members of patients, and is noted to segregate in a manner consistent with recessive inheritance. The variant was absent from 360 control individuals and from at least 300 control chromosomes, but is reported at a frequency of 0.00013 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence, the p.Ile2957Thr variant is classified as pathogenic for autosomal recessive polycystic kidney disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
GeneDx RCV000521323 SCV000617329 pathogenic not provided 2017-08-08 criteria provided, single submitter clinical testing The I2957T variant in the PKHD1 gene has been reported previously in the heterozygous state with another disease-causing variant in patients with ARPKD (Onuchic et al., 2002; Bergmann et al., 2003; Bergmann et al., 2004; Sharp et al., 2005; Denamur et al., 2010; Gunay-Aygun et al., 2010; Melchionda et al., 2016). The I2957T variant is observed in 9/66714 (0.013%) alleles from individuals of non-Finnish European background in the ExAC dataset (Lek et al., 2016). The I2957T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Isoleucine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret I2957T as a pathogenic variant.
Invitae RCV000390646 SCV000629936 pathogenic Autosomal recessive polycystic kidney disease 2019-09-05 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 2957 of the PKHD1 protein (p.Ile2957Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs760222236, ExAC 0.01%). This variant has been reported in many individuals affected with polycystic kidney disease (PMID: 11919560, 15805161, 19914852, 27225849). In at least three individuals, the variant was determined to be on the opposite chromosome (in trans) from pathogenic variants in multiple individuals affected with polycystic kidney disease (PMID: 11898128, 12506140, 15698423). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 357423). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000390646 SCV000699885 pathogenic Autosomal recessive polycystic kidney disease 2017-01-23 criteria provided, single submitter clinical testing Variant summary: The PKHD1 c.8870T>C (p.Ile2957Thr) variant involves the alteration of a conserved nucleotide, which 3/4 in silico tools predict damaging outcome for this variant. This variant was found in 10/122220 control chromosomes at a frequency of 0.0000818, which does not exceed the estimated maximal expected allele frequency of a pathogenic PKHD1 variant (0.0070711). In literature, this variant is widely reported as a pathogenic variant and is found in several patients with autosomal recessive polycystic kidney disease with consistent genotype-phenotype evidences. Available patient data show that this variant is a severe mutation. A patient who carried 10627delT and p.I2957T variants was found to have no ARPKD protein (i.e. fibronectin), strongly suggesting that this variant leads to functional impairment (Ward_2003). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.
Baylor Genetics RCV000390646 SCV001163022 pathogenic Autosomal recessive polycystic kidney disease criteria provided, single submitter clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.