Submissions for variant NM_138694.4(PKHD1):c.5360G>T (p.Cys1787Phe)

gnomAD frequency: 0.00002  dbSNP: rs367970695

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute for Human Genetics and Genomic Medicine, Uniklinik RWTH Aachen	RCV001751808	SCV001994883	uncertain significance	Polycystic kidney disease 4	2021-11-02	criteria provided, single submitter	clinical testing	The detected change is reported in the dbSNP database (dbSNP150, status October 28, 2021) with the designation rs367970695. In gnomAD it is listed with a frequency of 0.001769% (5/282592) (as of October 28, 2021). In the literature it has already been described in a patient with ARPKD in combination with a pathogenic variant (Losekoot et al., 2005). In terms of bio-informatics, the change is classified as “likely disease causing” (PolyPhen2, Mutation Taster, SIFT). Based on the current state of knowledge, the variant is to be classified as a "variant of uncertain significance" (ACMG criteria).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323914	SCV004029910	uncertain significance	not specified	2023-07-28	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.5360G>T (p.Cys1787Phe) 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 1.6e-05 in 251208 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5360G>T has been reported in the literature as a compound heterozygous genotype in two individuals affected with Polycystic Kidney And Hepatic Disease and as an uninformative genotype (i.e. zygosity not specified) or in the heterozygous state in several other affected individuals (e.g. Losekoot_2005, Bergmann_2005, Burgmaier_2021). These data do not allow any conclusion about variant significance. 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, 16133180). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV003329410	SCV004036936	uncertain significance	not provided	2023-09-08	criteria provided, single submitter	clinical testing	Observed heterozygous with no other PKHD1 variant in a family with polycystic kidney disease in published literature (Bergmann C et al., 2005); 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: 8740301, 15698423, 16133180, 33940108)
Baylor Genetics	RCV001751808	SCV004202244	likely pathogenic	Polycystic kidney disease 4	2023-10-14	criteria provided, single submitter	clinical testing
Invitae	RCV003502598	SCV004275660	likely pathogenic	Autosomal recessive polycystic kidney disease	2024-01-10	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 1787 of the PKHD1 protein (p.Cys1787Phe). This variant is present in population databases (rs367970695, gnomAD 0.003%). This missense change has been observed in individuals with polycystic kidney disease (PMID: 15698423, 16133180, 33940108). ClinVar contains an entry for this variant (Variation ID: 1255539). 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.
Laboratory of Gastroenterology and Hepatology, Radboud University Medical Center	RCV001844868	SCV001876979	uncertain significance	Autosomal dominant polycystic kidney disease	2021-09-01	no assertion criteria provided	research