ClinVar Miner

Submissions for variant NM_138694.4(PKHD1):c.2414C>T (p.Pro805Leu)

gnomAD frequency: 0.00004  dbSNP: rs199531851
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics RCV000432815 SCV000511810 pathogenic not provided 2017-01-06 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000432815 SCV000699857 uncertain significance not provided 2016-08-18 criteria provided, single submitter clinical testing Variant summary: The PKHD1 c.2414C>T (p.Pro805Leu) variant causes a missense change involving a conserved nucleotide with 3/4 in silico tools (SNPs&GO not captured due to low reliability index) predicting a "damaging" outcome, although these predictions have yet to be functionally assessed. This variant is not located in any known domain (InterPro, UniProt). The variant of interest was observed in the large broad control population from ExAC with an allele frequency of 7/121380 (0.0000575; 1/17340), which does not exceed the estimated maximal expected allele frequency for a pathogenic PKHD1 variant (0.0070711; 1/141). The variant of interest has been reported in multiple affected individuals in literature; however, all affected individuals have been found to carry another PKHD1 variant I3177T in the same allele. The complex p.[P805L;I3177T] is likely to be pathogenic based on family data but pathogenicity of p.P805L in isolation is unclear at this time. In a study, authors opine that the variant I3177T is the deleterious variant in the complex due to the fact that I3177T in isolation have been reported affected individuals whereas the p.P805L in isolation has yet to be reported in affected individuals. A clinical laboratory in 2012 reported the variant as pathogenic. Whether this variant is a modifier or a mild potentially pathogenic variant needs to be further studied by co-segregation and/or functional studies. Taken together, the variant of interest has currently been classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
Baylor Genetics RCV001004207 SCV001163055 pathogenic Autosomal recessive polycystic kidney disease criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001004207 SCV001236493 uncertain significance Autosomal recessive polycystic kidney disease 2024-01-21 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 805 of the PKHD1 protein (p.Pro805Leu). This variant is present in population databases (rs199531851, gnomAD 0.01%). This variant has been observed on the same chromosome with another PKHD1 variant (p.Ile3177Thr) in individuals affected with polycystic kidney disease (PMID: 16133180, 15108281, 18503009, 19940839). The haplotype (Pro805Leu; Ile3177Thr) has been observed on the opposite chromosome from other pathogenic variants in an individuals affected with polycystic kidney disease (PMID: 12846734, 15108281, Invitae). ClinVar contains an entry for this variant (Variation ID: 377354). 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 available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Mayo Clinic Laboratories, Mayo Clinic RCV000432815 SCV001713350 likely pathogenic not provided 2019-11-25 criteria provided, single submitter clinical testing PM2, PM3, PP1, PP4, PP5
GeneDx RCV000432815 SCV001766777 likely pathogenic not provided 2021-03-22 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30507656, 30650191, 19940839, 18503009, 15108281, 16133180, 15698423, 12846734, 19914852, 15108277, 12506140)
Baylor Genetics RCV003152602 SCV003841195 uncertain significance Polycystic kidney disease 4 2023-11-16 criteria provided, single submitter clinical testing
Gharavi Laboratory, Columbia University RCV000432815 SCV000920667 uncertain significance not provided 2018-09-16 no assertion criteria provided research

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