Submissions for variant NM_138694.4(PKHD1):c.12027C>G (p.Tyr4009Ter)

gnomAD frequency: 0.00100  dbSNP: rs143616240

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000589131	SCV000231963	uncertain significance	not provided	2015-05-22	criteria provided, single submitter	clinical testing
GeneDx	RCV000589131	SCV000565376	uncertain significance	not provided	2024-09-03	criteria provided, single submitter	clinical testing	Identified as a heterozygous variant in a patient diagnosed at birth with autosomal recessive polycystic kidney disease (ARPKD) in published literature, although a second PKHD1 variant was not identified (PMID: 15108281); Identified as a heterozygous PKHD1 variant in a patient with polycystic liver disease in published literature (PMID: 28375157); Nonsense variant predicted to result in protein truncation, as the last 66 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 15108277, 34426522, 33226606, 28375157, 15108281, 38374194, 31308072, 33742171)
Genetic Services Laboratory, University of Chicago	RCV000179675	SCV000596427	uncertain significance	not specified	2016-11-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000179675	SCV000699847	uncertain significance	not specified	2019-04-17	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.12027C>G (p.Tyr4009X) results in a premature termination codon in the last exon of the transcript, 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. If a stable protein product is made, this nonsense substitution would truncate the protein at codon 4009, which is 66 amino acids from the end of the protein. Truncations downstream of this position have been reported in the literature in two patients (c.12186delT/p.His4063Ilefs*22, PMID 19940839 and c.12036delA/p.Gly4013Alafs*25, PMID 29956005), where one of these individuals had an attenuated phenotype, indicating that a c-terminally truncated fibrocystin could be partially functional (PMID29956005). To our knowledge, no other truncating variants down stream to the variant of interest have been reported in the literature (HGMD), so the significance of a truncation variant in the C-terminal portion of this protein is not known. The variant allele was found at a frequency of 0.00035 in 251214 control chromosomes, predominantly at a frequency of 0.0026 within the African or African-American subpopulation in the gnomAD database. This frequency is not higher than expected for a pathogenic variant in PKHD1 causing Polycystic Kidney and Hepatic Disease (0.0026 vs 0.0071), allowing no conclusion about variant significance. In addition, at least one known pathogenic PKHD1 variant (c.1486C>T/p.Arg496X) was identified in the gnomAD database at a frequency that is higher than the variant of interest (i.e. 0.0068 in the European Finnish subpopulation), thus it cannot be concluded that c.12027C>G is benign in nature. The variant, c.12027C>G, has been reported in the literature heterozygous state (i.e. without identifying a variant in trans) in two patients, one of them was suspected to be affected with Polycystic Kidney and Hepatic Disease (Bergmann 2004), while the other had isolated polycystic liver disease (Besse 2017). Of note, copy number variants were not tested in these studies therefore these data do not allow clear conclusions about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Counsyl	RCV000674658	SCV000800034	uncertain significance	Autosomal recessive polycystic kidney disease	2018-05-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000674658	SCV001003760	likely benign	Autosomal recessive polycystic kidney disease	2024-01-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000674658	SCV001321611	likely benign	Autosomal recessive polycystic kidney disease	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000589131	SCV005197169	uncertain significance	not provided	2022-05-27	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000589131	SCV005407823	uncertain significance	not provided	2024-07-09	criteria provided, single submitter	clinical testing	BP2, PM3_supporting, PVS1_moderate
Genomics And Bioinformatics Analysis Resource, Columbia University	RCV003319328	SCV004024106	likely pathogenic	Polycystic kidney disease 4		no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV003937626	SCV004764511	uncertain significance	PKHD1-related disorder	2024-04-11	no assertion criteria provided	clinical testing	The PKHD1 c.12027C>G variant is predicted to result in premature protein termination (p.Tyr4009*). This variant has been previously reported in the heterozygous state and paternally inherited in an individual diagnosed with polycystic kidney disease (Bergmann et al. 2004. PubMed ID: 15108281). No second variant was reported in the individual, and no functional studies were performed to establish pathogenicity. This variant has also been reported in the heterozygous state in an individual from a cohort of patients with isolated polycystic liver disease who did not present with liver or kidney cysts (L-1224, Besse et al. 2017. PubMed ID: 28375157). Recently, this variant was observed in the compound heterozygous state in a cohort of individuals with chronic kidney disease; and, reported as a variant of uncertain significance (Vaisitti et al. 2021. PubMed ID: 33226606). This variant resides in the final exon of PKHD1 gene, and based on the current knowledge it is unclear if the resulting mRNA would undergo nonsense-mediated decay. This variant is present at a relatively high minor allele frequency of up to ~0.28% in the African sub-population in gnomAD, including one homozygous individual. Given the higher-than-expected minor allele frequency and uncertainty of a nonsense variant in the last exon, we classify this variant as uncertain.