Submissions for variant NM_138694.4(PKHD1):c.8824C>T (p.Arg2942Ter)

gnomAD frequency: 0.00001  dbSNP: rs398124500

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169555	SCV000221047	likely pathogenic	Autosomal recessive polycystic kidney disease	2015-01-16	criteria provided, single submitter	literature only
Eurofins Ntd Llc (ga)	RCV000790758	SCV000231408	pathogenic	not provided	2012-08-30	criteria provided, single submitter	clinical testing
Invitae	RCV000169555	SCV001211244	pathogenic	Autosomal recessive polycystic kidney disease	2024-01-12	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg2942*) 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 (rs398124500, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with polycystic kidney disease (PMID: 19940839). ClinVar contains an entry for this variant (Variation ID: 96439). For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000169555	SCV001427136	pathogenic	Autosomal recessive polycystic kidney disease	2018-11-23	criteria provided, single submitter	clinical testing	A heterozygous nonsense variant, NM_138694.3(PKHD1):c.8824C>T, has been identified in exon 57 of 67 of the PKHD1 gene. The variant is predicted to result in a premature stop codon at position 2942 of the protein (NP_619639.3(PKHD1):p.(Arg2942*)). This variant is predicted to result in loss of protein function through nonsense mediated decay, which is a reported mechanism of pathogenicity for this gene. The variant is present in the gnomAD database at a frequency of 0.0007% (2 heterozygotes, 0 homozygotes). It has been previously described as pathogenic in patients with Polycystic kidney disease (ClinVar, Denamur, E et al (2010)). And many other pathogenic LoF variants in the region have also been reported (ClinVar). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169555	SCV002547680	pathogenic	Autosomal recessive polycystic kidney disease	2022-05-27	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.8824C>T (p.Arg2942X) 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 250982 control chromosomes. c.8824C>T has been reported in the literature in individuals affected with Polycystic Kidney And Hepatic Disease. These data indicate that the variant may 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.
Baylor Genetics	RCV003474684	SCV004202264	pathogenic	Polycystic kidney disease 4	2023-10-02	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000169555	SCV001455062	pathogenic	Autosomal recessive polycystic kidney disease	2020-09-16	no assertion criteria provided	clinical testing