ClinVar Miner

Submissions for variant NM_138694.4(PKHD1):c.2414C>T (p.Pro805Leu) (rs199531851)

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Total submissions: 6
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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
Invitae RCV001004207 SCV001236493 uncertain significance Autosomal recessive polycystic kidney disease 2020-10-08 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 805 of the PKHD1 protein (p.Pro805Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs199531851, ExAC 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). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). 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
Gharavi Laboratory,Columbia University RCV000432815 SCV000920667 uncertain significance not provided 2018-09-16 no assertion criteria provided research

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