Submissions for variant NM_138694.4(PKHD1):c.5323C>T (p.Arg1775Ter)

gnomAD frequency: 0.00001  dbSNP: rs770522674

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000664790	SCV000788805	pathogenic	Autosomal recessive polycystic kidney disease	2016-12-16	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000664790	SCV000916153	pathogenic	Autosomal recessive polycystic kidney disease	2018-01-31	criteria provided, single submitter	clinical testing	The PKHD1 c.5323C>T (p.Arg1775Ter) variant is a stop-gained variant that is predicted to result in premature termination of the protein. This variant has been reported in three studies and is found in eight individuals with autosomal recessive polycystic kidney disease, including in a homozygous state in one individual, in a compound heterozygous state in five individuals (two of whom are siblings), and in a heterozygous state with a second unidentified variant in three individuals (Bergmann et al. 2005; Obeidova et al. 2015; Melchionda et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.000015 in the European (non-Finnish) population of the Exome Aggregation Consortium, though this is based on one allele in a region of good sequence coverage so the variant is presumed to be rare. Based on the evidence and due to the potential impact of stop-gained variants, the p.Arg1775Ter variant is classified as pathogenic for autosomal recessive polycystic kidney disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Baylor Genetics	RCV000664790	SCV001163044	pathogenic	Autosomal recessive polycystic kidney disease		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000664790	SCV001623346	pathogenic	Autosomal recessive polycystic kidney disease	2021-04-18	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.5323C>T (p.Arg1775X) 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 4e-06 in 251236 control chromosomes. c.5323C>T has been reported in the literature in multiple individuals affected with Polycystic Kidney And Hepatic Disease (example, Bergmann_2005, Melchionda_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two 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. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV002305527	SCV002599748	pathogenic	not provided	2022-10-26	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 significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 32574212, 30275481, 33059727, 15698423, 27225849)
Fulgent Genetics, Fulgent Genetics	RCV002507150	SCV002811647	pathogenic	Polycystic kidney disease 4	2022-01-08	criteria provided, single submitter	clinical testing
Invitae	RCV000664790	SCV003439361	pathogenic	Autosomal recessive polycystic kidney disease	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1775*) 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). 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. This premature translational stop signal has been observed in individual(s) with polycystic kidney disease (PMID: 15698423, 32574212, 33059727). ClinVar contains an entry for this variant (Variation ID: 550139). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV002507150	SCV004204656	pathogenic	Polycystic kidney disease 4	2023-05-20	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000664790	SCV002078083	pathogenic	Autosomal recessive polycystic kidney disease	2017-08-31	no assertion criteria provided	clinical testing