Submissions for variant NM_138694.4(PKHD1):c.9152T>C (p.Ile3051Thr)

gnomAD frequency: 0.00001  dbSNP: rs1374086784

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001293533	SCV001482127	uncertain significance	not specified	2023-08-16	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.9152T>C (p.Ile3051Thr) results in a non-conservative amino acid change located in the Right handed beta helix domain (IPR039448) 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 4e-06 in 251058 control chromosomes (gnomAD). c.9152T>C has been reported in the literature in individuals affected with Polycystic Kidney And Hepatic Disease (e.g. Bergmann_2005, Melchionda_2016, Burgmaier_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 15698423, 33940108, 27225849). Two ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic, and one classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Invitae	RCV001830113	SCV003439426	likely pathogenic	Autosomal recessive polycystic kidney disease	2022-01-13	criteria provided, single submitter	clinical testing	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. 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: 997896). This missense change has been observed in individual(s) with clinical features of autosomal recessive polycystic kidney disease (PMID: 15698423, 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 (no rsID available, gnomAD 0.0009%). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 3051 of the PKHD1 protein (p.Ile3051Thr).
GeneDx	RCV003320820	SCV004025536	likely pathogenic	not provided	2023-10-02	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; Identified with a second PKHD1 variant in an additional patient with ARPKD in published literature (Burgmaier et al., 2021); This variant is associated with the following publications: (PMID: 27225849, 33940108, 15698423)
Natera, Inc.	RCV001830113	SCV002077960	uncertain significance	Autosomal recessive polycystic kidney disease	2019-04-15	no assertion criteria provided	clinical testing