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

dbSNP: rs797045101

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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
Eurofins Ntd Llc (ga)	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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000190615	SCV001361899	likely pathogenic	Autosomal recessive polycystic kidney disease	2021-10-27	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. Additionally, trunctations in this gene have been associated with Polycystic Kidney And Hepatic Disease (Denamur_2010). The variant was absent in 250880 control chromosomes (gnomAD). c.9559delT has been reported in the literature in an individual affected with Polycystic Kidney And Hepatic Disease (Mansilla_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and have classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae	RCV000190615	SCV001591376	pathogenic	Autosomal recessive polycystic kidney disease	2022-08-21	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 208604). This variant has not been reported in the literature in individuals affected with PKHD1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser3187Leufs*33) 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).
Baylor Genetics	RCV003462297	SCV004204724	likely pathogenic	Polycystic kidney disease 4	2023-02-22	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV003462297	SCV004238585	likely pathogenic	Polycystic kidney disease 4	2023-07-11	criteria provided, single submitter	clinical testing