Submissions for variant NM_138694.4(PKHD1):c.2341C>T (p.Arg781Ter)

gnomAD frequency: 0.00004  dbSNP: rs398124478

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000788487	SCV000228089	pathogenic	not provided	2015-12-16	criteria provided, single submitter	clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000176433	SCV000680339	pathogenic	Autosomal recessive polycystic kidney disease	2017-12-07	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000176433	SCV000743917	pathogenic	Autosomal recessive polycystic kidney disease	2014-10-08	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000176433	SCV000894384	pathogenic	Autosomal recessive polycystic kidney disease	2018-10-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000176433	SCV000919997	pathogenic	Autosomal recessive polycystic kidney disease	2018-03-19	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.2341C>T (p.Arg781X) 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. The variant allele was found at a frequency of 4.1e-05 in 246784 control chromosomes (in gnomAD and publication data). This frequency is not significantly higher than expected for a pathogenic variant in PKHD1 causing Polycystic Kidney and Hepatic Disease (4.1e-05 vs 7.10e-03), allowing no conclusion about variant significance. c.2341C>T has been reported in the literature in multiple individuals affected with Polycystic Kidney and Hepatic Disease (e.g. Sharp 2005, Bergmann 2005, Losekoot 2005). 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, and both of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Blueprint Genetics	RCV000788487	SCV000927625	pathogenic	not provided	2018-04-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000176433	SCV001163056	pathogenic	Autosomal recessive polycystic kidney disease		criteria provided, single submitter	clinical testing
GeneDx	RCV000788487	SCV001167697	pathogenic	not provided	2023-07-20	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, 23891399, 15805161, 24710345, 15698423, 16133180, 29956005, 19940839, 19914852, 30275481, 31395954, 28578020, 33123899, 32359821, 32939031, 31328266, 35768702)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000176433	SCV001202272	pathogenic	Autosomal recessive polycystic kidney disease	2024-01-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg781*) 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 (rs398124478, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with polycystic kidney disease (PKD) and features suggestive of PKD (PMID: 15805161, 24710345, 28578020, 29956005). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 96387). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000176433	SCV001427170	pathogenic	Autosomal recessive polycystic kidney disease	2019-01-07	criteria provided, single submitter	clinical testing	A heterozygous nonsense variant, NM_138694.3(PKHD1):c.2341C>T, has been identified in exon 23 of 67 of the PKHD1 gene. The variant is predicted to result in a premature stop codon at position 781 of the protein (NP_619639.3(PKHD1):p.(Arg781*)). 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 0.004% (10 heterozygotes, 0 homozygotes). The variant has been previously described as pathogenic in multiple patients with autosomal recessive kidney disease (ClinVar, Sharp, A. M., et al. (2005), Hao, X., et al. (2014), Bullich, G., et al. (2018)). Many upstream and downstream variants resulting in a premature termination codon have been reported in patients with polycystic kidney disease (ClinVar). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262428	SCV001440293	pathogenic	Polycystic kidney disease 4	2019-01-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001262428	SCV001752808	pathogenic	Polycystic kidney disease 4	2021-06-30	criteria provided, single submitter	clinical testing
Lifecell International Pvt. Ltd	RCV001262428	SCV003924415	pathogenic	Polycystic kidney disease 4		criteria provided, single submitter	clinical testing	A Homozygote Nonsense variant c.2341C>T in Exon 23 of the PKHD1 gene that results in the amino acid substitution p.Arg781* was identified. The observed variant has a maximum allele frequency of 0.00004/0.00 % in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. This sequence change creates a premature translational stop signal (p.Arg781*) 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 (Denamur E et al., 2010). This premature translational stop signal has been observed in individual(s) with polycystic kidney disease (PKD) and features suggestive of PKD (Sharp AM et al., 2005, Hao X et al., 2014). ClinVar has also classified this variant as Pathogenic (ClinVar ID: 96387). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.
Baylor Genetics	RCV001262428	SCV004202231	pathogenic	Polycystic kidney disease 4	2024-03-20	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000788487	SCV005413733	pathogenic	not provided	2023-09-29	criteria provided, single submitter	clinical testing	PM2_moderate, PM3, PVS1
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000176433	SCV000745893	pathogenic	Autosomal recessive polycystic kidney disease	2016-03-14	no assertion criteria provided	clinical testing
Laboratory of Gastroenterology and Hepatology, Radboud University Medical Center	RCV001844805	SCV001876978	pathogenic	Autosomal dominant polycystic kidney disease	2021-09-01	no assertion criteria provided	research
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000788487	SCV001952456	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000788487	SCV001972682	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000176433	SCV002081033	pathogenic	Autosomal recessive polycystic kidney disease	2017-08-31	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004748567	SCV005346377	pathogenic	PKHD1-related disorder	2024-07-22	no assertion criteria provided	clinical testing	The PKHD1 c.2341C>T variant is predicted to result in premature protein termination (p.Arg781*). This variant was reported in individuals with autosomal recessive polycystic kidney disease (ARPKD) (Sharp et al. 2005. PubMed ID: 15805161; Hao et al. 2014. PubMed ID: 24710345; Fang et al. 2017. PubMed ID: 28578020). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD. Nonsense variants in PKHD1 are expected to be pathogenic. This variant is interpreted as pathogenic.