Submissions for variant NM_138694.4(PKHD1):c.8518C>T (p.Arg2840Cys)

gnomAD frequency: 0.00006  dbSNP: rs200432861

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV000788914	SCV000928206	likely pathogenic	not provided	2019-02-05	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001004194	SCV001163027	pathogenic	Autosomal recessive polycystic kidney disease		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001004194	SCV001223477	pathogenic	Autosomal recessive polycystic kidney disease	2023-12-01	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2840 of the PKHD1 protein (p.Arg2840Cys). This variant is present in population databases (rs200432861, gnomAD 0.005%). This missense change has been observed in individuals with polycystic kidney disease (PMID: 15805161, 16133180, 30507656). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 636941). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PKHD1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001004194	SCV001519536	pathogenic	Autosomal recessive polycystic kidney disease	2021-03-09	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.8518C>T (p.Arg2840Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 249810 control chromosomes. c.8518C>T has been reported in the literature in multiple individuals affected with Polycystic Kidney And Hepatic Disease (Sharp_2005, Bergmann_2005, Denamur_2010, Losekoot_2005, Yang_2019). 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 likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV003472329	SCV004202207	pathogenic	Polycystic kidney disease 4	2024-02-17	criteria provided, single submitter	clinical testing
Laboratory of Gastroenterology and Hepatology, Radboud University Medical Center	RCV001844847	SCV001876968	likely pathogenic	Autosomal dominant polycystic liver disease	2021-09-01	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004748966	SCV005360818	pathogenic	PKHD1-related disorder	2024-06-14	no assertion criteria provided	clinical testing	The PKHD1 c.8518C>T variant is predicted to result in the amino acid substitution p.Arg2840Cys. This variant has been reported in the compound heterozygous state in multiple individuals with autosomal recessive polycystic kidney disease (ARPKD) and congenital hepatic fibrosis (CHF) (Sharp et al. 2005. PubMed ID: 15805161; Losekoot et al. 2005. PubMed ID: 16133180; Yang et al. 2018. PubMed ID: 30507656; Li et al. 2023. PubMed ID: 36835961) and has been shown to segregate with disease in at least 3 families (Losekoot et al. 2005. PubMed ID: 16133180; Yang et al. 2018. PubMed ID: 30507656). Furthermore, we have repeatedly found this variant in both the compound heterozygous and homozygous states in several presumably unrelated ARPKD patients at PreventionGenetics. This variant is reported in 0.0047% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.