ClinVar Miner

Submissions for variant NM_138694.4(PKHD1):c.2341C>T (p.Arg781Ter) (rs398124478)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000788487 SCV000228089 pathogenic not provided 2015-12-16 criteria provided, single submitter clinical testing
Institute of Human Genetics,Klinikum rechts der Isar RCV000176433 SCV000680339 pathogenic Autosomal recessive polycystic kidney disease 2017-12-07 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000176433 SCV000743917 pathogenic Autosomal recessive polycystic kidney disease 2014-10-08 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000176433 SCV000894384 pathogenic Autosomal recessive polycystic kidney disease 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000176433 SCV000919997 pathogenic Autosomal recessive polycystic kidney disease 2018-03-19 criteria provided, single submitter clinical testing Variant summary: PKHD1 c.2341C>T (p.Arg781X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4.1e-05 in 246784 control chromosomes (in gnomAD and publication data). This frequency is not significantly higher than expected for a pathogenic variant in PKHD1 causing Polycystic Kidney and Hepatic Disease (4.1e-05 vs 7.10e-03), allowing no conclusion about variant significance. c.2341C>T has been reported in the literature in multiple individuals affected with Polycystic Kidney and Hepatic Disease (e.g. Sharp 2005, Bergmann 2005, Losekoot 2005). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Blueprint Genetics RCV000788487 SCV000927625 pathogenic not provided 2018-04-11 criteria provided, single submitter clinical testing
Baylor Genetics RCV000176433 SCV001163056 pathogenic Autosomal recessive polycystic kidney disease criteria provided, single submitter clinical testing
GeneDx RCV000788487 SCV001167697 pathogenic not provided 2019-01-31 criteria provided, single submitter clinical testing The R781X variant in the PKHD1 gene has been reported previously in association with PKHD1-related disorders (Fang et al., 2017; Sharp et al., 2005; Hao et al., 2014). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R781X variant is observed in 10/246184 (0.004%) alleles in large population cohorts, and no individuals were reported to be homozygous (Lek et al., 2016). We interpret R781X as a pathogenic variant,
Invitae RCV000176433 SCV001202272 pathogenic Autosomal recessive polycystic kidney disease 2019-05-30 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg781*) in the PKHD1 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs398124478, ExAC 0.01%). This variant has been observed in individual(s) with polycystic kidney disease (PKD) (PMID: 15805161, 24710345, 29956005). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant was also reported to segregate in families with features suggestive of PKD (PMID: 28578020, 24710345). ClinVar contains an entry for this variant (Variation ID: 96387). Loss-of-function variants in PKHD1 are known to be pathogenic (PMID: 19940839). For these reasons, this variant has been classified as Pathogenic.
Genome Diagnostics Laboratory,VU University Medical Center Amsterdam RCV000176433 SCV000745893 pathogenic Autosomal recessive polycystic kidney disease 2016-03-14 no assertion criteria provided clinical testing

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