ClinVar Miner

Submissions for variant NM_138694.4(PKHD1):c.9559del (p.Ser3187fs) (rs797045101)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000190615 SCV000245650 pathogenic Autosomal recessive polycystic kidney disease 2014-12-30 criteria provided, single submitter clinical testing The p.Ser3187LeufsX33 variant in PKHD1 has not been previously reported in individuals with polycystic kidney disease and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 3187 and leads to a premature termination codon 33 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Complete loss of PKHD1 function is an established disease mechanism in polycystic kidney disease. In summary, this variant meets our criteria to be classified as pathogenic for polycystic kidney disease in an autosomal recessive manner (http://pcpgmwww.partners.org/personalizedmedicince/LMM) based upon the predicted impact of the variant.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000223998 SCV000280876 pathogenic not provided 2015-04-10 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000223998 SCV000860536 pathogenic not provided 2018-03-29 criteria provided, single submitter clinical testing
Baylor Genetics RCV000190615 SCV001163018 likely pathogenic Autosomal recessive polycystic kidney disease criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000190615 SCV001361899 likely pathogenic Autosomal recessive polycystic kidney disease 2019-05-16 criteria provided, single submitter clinical testing Variant summary: PKHD1 c.9559delT (p.Ser3187LeufsX33) 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 was absent in 250880 control chromosomes (gnomAD). To our knowledge, no occurrence of c.9559delT in individuals affected with Polycystic Kidney and Hepatic Disease and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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