ClinVar Miner

Submissions for variant NM_138694.4(PKHD1):c.10452dup (p.Leu3485fs) (rs771623148)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169490 SCV000220944 likely pathogenic Autosomal recessive polycystic kidney disease 2014-12-10 criteria provided, single submitter literature only
Integrated Genetics/Laboratory Corporation of America RCV000169490 SCV000918006 pathogenic Autosomal recessive polycystic kidney disease 2018-02-02 criteria provided, single submitter clinical testing Variant summary: PKHD1 c.10452dupT (p.Leu3485SerfsX18) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.10637delT/p.Val3546fsX22, c.11314C>T/p.Arg3772X). The variant allele was found at a frequency of 4.1e-06 in 245374 control chromosomes. c.10452dupT has been reported in the literature in individuals affected with Polycystic Kidney and Hepatic Disease. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory classified this variant as likely pathogenic. Many truncation variants downstream have been reported in affected individuals, such as c.10639dupC, c.11339dupC, c.11408dupA, and c.11538dupT, suggesting the functional importance of the C-terminal region of this protein. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000169490 SCV000946312 pathogenic Autosomal recessive polycystic kidney disease 2019-11-18 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Leu3485Serfs*18) in the PKHD1 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs771623148, ExAC 0.01%). This variant has been observed in individuals affected with autosomal recessive polycystic kidney disease (PMID: 15108281, 19914852). ClinVar contains an entry for this variant (Variation ID: 189084). Loss-of-function variants in PKHD1 are known to be pathogenic (PMID: 19940839). For these reasons, this variant has been classified as Pathogenic.
Department of Molecular and Human Genetics, Baylor College of Medicine RCV000169490 SCV001334117 pathogenic Autosomal recessive polycystic kidney disease 2020-04-16 criteria provided, single submitter clinical testing

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