Submissions for variant NM_138694.4(PKHD1):c.11074C>T (p.Arg3692Ter)

dbSNP: rs769559267

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000728802	SCV000856418	pathogenic	not provided	2017-08-16	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001004187	SCV001163012	pathogenic	Autosomal recessive polycystic kidney disease		criteria provided, single submitter	clinical testing
Invitae	RCV001004187	SCV001396959	pathogenic	Autosomal recessive polycystic kidney disease	2023-05-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg3692*) 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). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 593691). This premature translational stop signal has been observed in individual(s) with polycystic kidney disease (PMID: 12874454). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database.
Laboratory of Molecular Genetics, Children's Memorial Health Institute	RCV001004187	SCV001434240	likely pathogenic	Autosomal recessive polycystic kidney disease	2020-09-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001004187	SCV002571029	pathogenic	Autosomal recessive polycystic kidney disease	2022-07-14	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.11074C>T (p.Arg3692X) 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 allele was found at a frequency of 8e-06 in 251350 control chromosomes (gnomAD and publication data). c.11074C>T has been reported in the literature in individuals affected with Polycystic Kidney And Hepatic Disease (Furu_2003, Jung_2020, Wicher_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n-=4) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV003465658	SCV004204557	pathogenic	Polycystic kidney disease 4	2023-09-03	criteria provided, single submitter	clinical testing
Laboratory of Gastroenterology and Hepatology, Radboud University Medical Center	RCV001844843	SCV001876975	pathogenic	Autosomal dominant polycystic liver disease	2021-09-01	no assertion criteria provided	research
Natera, Inc.	RCV001004187	SCV002075493	pathogenic	Autosomal recessive polycystic kidney disease	2017-08-18	no assertion criteria provided	clinical testing