Submissions for variant NM_138694.4(PKHD1):c.2854G>A (p.Gly952Arg)

gnomAD frequency: 0.00002  dbSNP: rs773136605

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724042	SCV000228491	pathogenic	not provided	2014-06-05	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000724042	SCV000927782	pathogenic	not provided	2018-07-05	criteria provided, single submitter	clinical testing
Invitae	RCV000176777	SCV001199787	pathogenic	Autosomal recessive polycystic kidney disease	2023-08-04	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 196052). This missense change has been observed in individual(s) with polycystic kidney disease (PMID: 16133180, 27225849). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs773136605, gnomAD 0.01%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 952 of the PKHD1 protein (p.Gly952Arg).
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001198369	SCV001369281	likely pathogenic	Polycystic kidney disease 4	2019-12-11	criteria provided, single submitter	clinical testing	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM2,PP3.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000176777	SCV001737689	pathogenic	Autosomal recessive polycystic kidney disease	2021-05-21	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.2854G>A (p.Gly952Arg) results in a non-conservative amino acid change located in the IPT domain of 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 250594 control chromosomes. c.2854G>A has been reported in the literature in multiple individuals affected with Polycystic Kidney And Hepatic Disease (Losekoot_2005, Melchionda_2016, Yao_2021). 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. 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.
GeneDx	RCV000724042	SCV002525272	pathogenic	not provided	2022-06-03	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16133180, 27225849, 33845788)
Baylor Genetics	RCV001198369	SCV004202213	pathogenic	Polycystic kidney disease 4	2023-10-28	criteria provided, single submitter	clinical testing
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000176777	SCV000536850	likely pathogenic	Autosomal recessive polycystic kidney disease	2016-09-05	no assertion criteria provided	research
Laboratory of Gastroenterology and Hepatology, Radboud University Medical Center	RCV001844815	SCV001876987	likely pathogenic	Autosomal dominant polycystic liver disease	2021-09-01	no assertion criteria provided	research
Natera, Inc.	RCV000176777	SCV002081012	pathogenic	Autosomal recessive polycystic kidney disease	2020-12-21	no assertion criteria provided	clinical testing