ClinVar Miner

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

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000674658 SCV000800034 uncertain significance Autosomal recessive polycystic kidney disease 2018-05-18 criteria provided, single submitter clinical testing
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 RCV000589131 SCV000699847 uncertain significance not provided 2016-09-16 criteria provided, single submitter clinical testing Variant summary: The PKHD1 c.12027C>G (p.Tyr4009X) variant results in a premature termination codon in the last exon of the transcript, predicted to cause a truncated or absent PKHD1 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. While one in silico tool predicts a damaging outcome for this variant, there were no functional studies published at the time of variant classification. This variant was found in 49/121704 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.0025005 (26/10398). However, this frequency is lower than the estimated maximal expected allele frequency of a pathogenic PKHD1 variant (0.0070711). At least one known pathogenic PKHD1 variant (c.1486C>T/p.Arg496X) was identified in the ExAC database at a frequency higher than the variant of interest (69/121402 control chromosomes), thus it cannot be concluded that c.12027C>G is benign in nature. However, PKHD1 c.12027C>G (p.Tyr4009X) was identified in only one patient reported in the literature without a variant identified in trans (Bergmann_2004). Notably, only one other patient with a frame-shift mutation downstream of the variant of interest has been identified mutation (c.12186delT/p.L4062LfsIQYTRKLFRSNC; PMID: 19940839), and this individual also did not have a variant identified in trans. To our knowledge, no other truncation or frame-shift variants have been reported in the literature (HGMD), so the significance of a truncation variant in the C-terminal portion of protein is not known.In addition, at least one clinical diagnostic laboratory classified this variant as uncertain significance. Taken together, this variant is classified as VUS until additional information is available.

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