Submissions for variant NM_138694.4(PKHD1):c.10628_10635del (p.Leu3543fs)

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Total submissions: 5

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV001004188	SCV001163014	pathogenic	Autosomal recessive polycystic kidney disease		criteria provided, single submitter	clinical testing
Invitae	RCV001004188	SCV001208888	pathogenic	Autosomal recessive polycystic kidney disease	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu3543Cysfs*9) 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 (rs752889346, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with clinical features of autosomal recessive polycystic kidney disease (PMID: 19914852, 30650191). ClinVar contains an entry for this variant (Variation ID: 813372). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001004188	SCV001362929	likely pathogenic	Autosomal recessive polycystic kidney disease	2022-10-31	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.10628_10635delTGTATGTT (p.Leu3543CysfsX9) 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. The variant allele was found at a frequency of 4e-06 in 250198 control chromosomes. c.10628_10635delTGTATGTT has been reported in the literature in at least one individual affected with Polycystic Kidney And Hepatic Disease (Gunay-Aygun_2010) and in one fetus with isolated bilateral hyperechogenic kidneys (Shuster_2019). The variant was found in trans with other pathogenic/likely pathogenic variants in these patients (e.g. p.Ile222Val), providing moderate evidence of pathogenicity. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, classifying the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneDx	RCV003320778	SCV004025251	pathogenic	not provided	2023-08-08	criteria provided, single submitter	clinical testing	Frameshift 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 a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30650191, 19914852)
Baylor Genetics	RCV003467570	SCV004204761	pathogenic	Polycystic kidney disease 4	2022-11-06	criteria provided, single submitter	clinical testing

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