ClinVar Miner

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

gnomAD frequency: 0.00004  dbSNP: rs398124478
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Total submissions: 19
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000788487 SCV000228089 pathogenic not provided 2015-12-16 criteria provided, single submitter clinical testing
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München 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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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 2023-07-20 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 23891399, 15805161, 24710345, 15698423, 16133180, 29956005, 19940839, 19914852, 30275481, 31395954, 28578020, 33123899, 32359821, 32939031, 31328266, 35768702)
Invitae RCV000176433 SCV001202272 pathogenic Autosomal recessive polycystic kidney disease 2024-01-20 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. Loss-of-function variants in PKHD1 are known to be pathogenic (PMID: 19940839). This variant is present in population databases (rs398124478, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with polycystic kidney disease (PKD) and features suggestive of PKD (PMID: 15805161, 24710345, 28578020, 29956005). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 96387). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000176433 SCV001427170 pathogenic Autosomal recessive polycystic kidney disease 2019-01-07 criteria provided, single submitter clinical testing A heterozygous nonsense variant, NM_138694.3(PKHD1):c.2341C>T, has been identified in exon 23 of 67 of the PKHD1 gene. The variant is predicted to result in a premature stop codon at position 781 of the protein (NP_619639.3(PKHD1):p.(Arg781*)). This variant is predicted to result in loss of protein function through nonsense-mediated decay, which is a reported mechanism of pathogenicity for this gene. The variant is present in the gnomAD database at a frequency of 0.004% (10 heterozygotes, 0 homozygotes). The variant has been previously described as pathogenic in multiple patients with autosomal recessive kidney disease (ClinVar, Sharp, A. M., et al. (2005), Hao, X., et al. (2014), Bullich, G., et al. (2018)). Many upstream and downstream variants resulting in a premature termination codon have been reported in patients with polycystic kidney disease (ClinVar). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.
Institute of Human Genetics, University of Leipzig Medical Center RCV001262428 SCV001440293 pathogenic Polycystic kidney disease 4 2019-01-01 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV001262428 SCV001752808 pathogenic Polycystic kidney disease 4 2021-06-30 criteria provided, single submitter clinical testing
Lifecell International Pvt. Ltd RCV001262428 SCV003924415 pathogenic Polycystic kidney disease 4 criteria provided, single submitter clinical testing A Homozygote Nonsense variant c.2341C>T in Exon 23 of the PKHD1 gene that results in the amino acid substitution p.Arg781* was identified. The observed variant has a maximum allele frequency of 0.00004/0.00 % in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. 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. Loss-of-function variants in PKHD1 are known to be pathogenic (Denamur E et al., 2010). This premature translational stop signal has been observed in individual(s) with polycystic kidney disease (PKD) and features suggestive of PKD (Sharp AM et al., 2005, Hao X et al., 2014). ClinVar has also classified this variant as Pathogenic (ClinVar ID: 96387). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.
Baylor Genetics RCV001262428 SCV004202231 pathogenic Polycystic kidney disease 4 2023-10-20 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000176433 SCV000745893 pathogenic Autosomal recessive polycystic kidney disease 2016-03-14 no assertion criteria provided clinical testing
Laboratory of Gastroenterology and Hepatology, Radboud University Medical Center RCV001844805 SCV001876978 pathogenic Autosomal dominant polycystic kidney disease 2021-09-01 no assertion criteria provided research
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000788487 SCV001952456 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000788487 SCV001972682 pathogenic not provided no assertion criteria provided clinical testing
Natera, Inc. RCV000176433 SCV002081033 pathogenic Autosomal recessive polycystic kidney disease 2017-08-31 no assertion criteria provided clinical testing

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