ClinVar Miner

Submissions for variant NM_138694.4(PKHD1):c.11881C>T (p.Arg3961Ter)

gnomAD frequency: 0.00001  dbSNP: rs144193508
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000665966 SCV000790187 uncertain significance Autosomal recessive polycystic kidney disease 2017-03-07 criteria provided, single submitter clinical testing
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota RCV000665966 SCV000891316 likely pathogenic Autosomal recessive polycystic kidney disease 2017-09-06 criteria provided, single submitter clinical testing
Invitae RCV000665966 SCV000950755 pathogenic Autosomal recessive polycystic kidney disease 2024-01-29 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg3961*) in the PKHD1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 114 amino acid(s) of the PKHD1 protein. This variant is present in population databases (rs144193508, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with polycystic kidney disease (PMID: 34536170; Invitae). 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: 551016). This variant disrupts a region of the PKHD1 protein in which other variant(s) (p.Pro3968Leufs*70) have been observed in individuals with PKHD1-related conditions (PMID: 33940108). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV001784237 SCV001163007 likely pathogenic Polycystic kidney disease 4 2024-01-08 criteria provided, single submitter clinical testing
Revvity Omics, Revvity Omics RCV001784237 SCV002024647 likely pathogenic Polycystic kidney disease 4 2019-09-11 criteria provided, single submitter clinical testing
GeneDx RCV002245081 SCV002513635 likely pathogenic not provided 2022-05-10 criteria provided, single submitter clinical testing Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 114 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published in an individual with PKHD1-related disease as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 22034641, 30275481, 27535533)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV001784237 SCV002769164 uncertain significance Polycystic kidney disease 4 2020-05-21 criteria provided, single submitter clinical testing A heterozygous nonsense variant, NM_138694.3(PKHD1):c.11881C>T, has been identified in exon 67 of 67 of the PKHD1 gene. The variant is predicted to result in a premature stop codon at position 3961 of the protein (NP_619639.3(PKHD1):p.(Arg3961*)). This variant is predicted to result in loss of protein function through truncation (although no known functional domains are affected). The variant is present in the gnomAD database at a frequency of 0.0024% (6 heterozygotes, 0 homozygotes). This variant has not been previously reported in clinical cases. Based on the information available at the time of curation, this variant has been classified as VARIANT of UNCERTAIN SIGNIFICANCE (VUS) with POTENTIAL CLINICAL RELEVANCE.
Natera, Inc. RCV000665966 SCV001455046 uncertain significance Autosomal recessive polycystic kidney disease 2020-09-16 no assertion criteria provided clinical testing

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