Submissions for variant NM_138694.4(PKHD1):c.1774C>T (p.Arg592Ter)

gnomAD frequency: 0.00003  dbSNP: rs779050294

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781727	SCV000919996	pathogenic	Autosomal recessive polycystic kidney disease	2022-10-17	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.1774C>T (p.Arg592X) 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 250256 control chromosomes. c.1774C>T has been reported in the literature as biallelic compound heterozygous genotypes in multiple individuals affected with Polycystic Kidney And Hepatic Disease (example, Sharp_2005, Wojcik_2019, Hu_2018, Burgmaier_2021, Kucinska-Chahwan_2022). These data indicate that the variant is likely to be associated with disease. Four 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 pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000781727	SCV001587469	pathogenic	Autosomal recessive polycystic kidney disease	2022-08-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg592*) 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). This variant is present in population databases (rs779050294, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with autosomal recessive polycystic kidney disease (PMID: 15805161, 31395954). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 633358). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV001507664	SCV001713351	pathogenic	not provided	2020-04-24	criteria provided, single submitter	clinical testing	PM2, PVS1
GeneDx	RCV001507664	SCV002521987	pathogenic	not provided	2022-05-18	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 12874454, 31395954, 15805161)
Fulgent Genetics, Fulgent Genetics	RCV002477789	SCV002788732	likely pathogenic	Polycystic kidney disease 4	2022-03-03	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV002477789	SCV004204758	pathogenic	Polycystic kidney disease 4	2022-11-10	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000781727	SCV001463320	likely pathogenic	Autosomal recessive polycystic kidney disease	2020-09-16	no assertion criteria provided	clinical testing