Submissions for variant NM_138694.4(PKHD1):c.5129C>T (p.Pro1710Leu)

gnomAD frequency: 0.00006  dbSNP: rs749294509

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000665691	SCV000789852	uncertain significance	Autosomal recessive polycystic kidney disease	2017-02-23	criteria provided, single submitter	clinical testing
Invitae	RCV000665691	SCV000819622	likely pathogenic	Autosomal recessive polycystic kidney disease	2024-01-07	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1710 of the PKHD1 protein (p.Pro1710Leu). This variant is present in population databases (rs749294509, gnomAD 0.007%). This missense change has been observed in individual(s) with polycystic kidney disease (PMID: 27225849). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 550835). 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%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001293534	SCV001482128	uncertain significance	not specified	2021-02-01	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.5129C>T (p.Pro1710Leu) 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 5.2e-05 in 251316 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in PKHD1 causing Polycystic Kidney And Hepatic Disease (5.2e-05 vs 0.0071), allowing no conclusion about variant significance. c.5129C>T has been reported in the literature in at least one individual affected with Polycystic Kidney And Hepatic Disease (e.g. Melchionda_2016). This report does not provide unequivocal conclusions about association of the variant with Polycystic Kidney And Hepatic Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV001526534	SCV001736956	likely pathogenic	Renal cyst		criteria provided, single submitter	clinical testing
GeneDx	RCV003442011	SCV004170202	uncertain significance	not provided	2023-10-24	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: 27225849)
Natera, Inc.	RCV000665691	SCV001459195	uncertain significance	Autosomal recessive polycystic kidney disease	2020-09-16	no assertion criteria provided	clinical testing