ClinVar Miner

Submissions for variant NM_138694.4(PKHD1):c.12027C>G (p.Tyr4009Ter) (rs143616240)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000589131 SCV000231963 uncertain significance not provided 2015-05-22 criteria provided, single submitter clinical testing
GeneDx RCV000589131 SCV000565376 uncertain significance not provided 2018-11-01 criteria provided, single submitter clinical testing The Y4009X variant in the PKHD1 gene has been reported previously as heterozygous with no second variant identified in a newborn with pepper and salt" pattern on ultrasound, enlarged kidneys, and respiratory distress. The newborn was diagnosed at birth with autosomal recessive polycystic kidney disease and died in the perinatal period (Bergmann et al., 2004). The Y4009X variant was also identified in the heterozygous state without an identified second variant in an individual with polycystic liver disease (Besse et al., 2017). This variant is predicted to cause loss of normal protein function through protein truncation. The Y4009X variant is observed in 61/24034 (0.25%) alleles from individuals of African background in large population cohorts, and no individuals were reported to be homozygous (Lek et al., 2016). We interpret Y4009X as a variant of uncertain significance."
Genetic Services Laboratory, University of Chicago RCV000179675 SCV000596427 uncertain significance not specified 2016-11-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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
Invitae RCV000674658 SCV001003760 likely benign Autosomal recessive polycystic kidney disease 2019-12-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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.

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