Submissions for variant NM_138694.4(PKHD1):c.6116T>C (p.Leu2039Pro)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003123546	SCV003801269	uncertain significance	not specified	2023-01-26	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.6116T>C (p.Leu2039Pro) results in a non-conservative amino acid change located in the G8 domain (IPR019316) 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 251312 control chromosomes (gnomAD). c.6116T>C has been reported in the literature in individuals affected with Polycystic Kidney And Hepatic Disease (example: Krall_2014). 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Baylor Genetics	RCV003459782	SCV004204566	likely pathogenic	Polycystic kidney disease 4	2023-08-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003502692	SCV004293751	pathogenic	Autosomal recessive polycystic kidney disease	2023-11-06	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 2039 of the PKHD1 protein (p.Leu2039Pro). This variant is present in population databases (rs777228780, gnomAD 0.0009%). This missense change has been observed in individual(s) with polycystic kidney disease (PMID: 24162162). 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: 2429307). 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.