Submissions for variant NM_138694.4(PKHD1):c.7964A>C (p.His2655Pro)

gnomAD frequency: 0.00002  dbSNP: rs748196998

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV002273390	SCV002558124	likely pathogenic	not provided	2022-04-07	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: 26673778, 33059616)
Invitae	RCV003096155	SCV003466771	pathogenic	Autosomal recessive polycystic kidney disease	2023-11-17	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 2655 of the PKHD1 protein (p.His2655Pro). This variant is present in population databases (rs748196998, gnomAD 0.0009%). This missense change has been observed in individual(s) with polycystic kidney disease (PMID: 26673778, 33059616). 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: 1699533). 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	RCV003235695	SCV003934196	uncertain significance	not specified	2023-05-10	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.7964A>C (p.His2655Pro) 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 4e-06 in 251258 control chromosomes. c.7964A>C has been reported in the literature in individuals affected with Polycystic Kidney And Hepatic Disease and related conditions (Schueler_2016, Molinari_2020). 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: 33059616, 26673778).Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and one classified the variant as pathogenic and other as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Baylor Genetics	RCV003471302	SCV004204581	likely pathogenic	Polycystic kidney disease 4	2023-08-16	criteria provided, single submitter	clinical testing