Submissions for variant NM_138694.4(PKHD1):c.6074A>G (p.Tyr2025Cys)

dbSNP: rs1554144226

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000667357	SCV000791791	uncertain significance	Autosomal recessive polycystic kidney disease	2017-05-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000667357	SCV001572406	likely pathogenic	Autosomal recessive polycystic kidney disease	2021-04-06	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.6074A>G (p.Tyr2025Cys) 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 was absent in 251546 control chromosomes (gnomAD and publication data). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6074A>G has been reported in the literature in at-least one case of a proband affected with features of autosomal recessive polycystic kidney disease to include kidney and liver involvement (PKD/CHF), pulmonary hypoplasia, oligohydramnios and perinatal death (Krall_2014). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneDx	RCV003442013	SCV004169431	likely pathogenic	not provided	2023-05-11	criteria provided, single submitter	clinical testing	Identified in the presence of a second PKHD1 variant, phase unknown, in a patient with polycystic kidney disease in published literature (Krall et al., 2014); 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: 24162162)
Invitae	RCV000667357	SCV004293753	likely pathogenic	Autosomal recessive polycystic kidney disease	2023-08-21	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 2025 of the PKHD1 protein (p.Tyr2025Cys). This variant is not present in population databases (gnomAD no frequency). 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: 552140). 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. 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.