Submissions for variant NM_138694.4(PKHD1):c.6629G>A (p.Gly2210Glu)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV003109896	SCV003761652	uncertain significance	not provided	2022-07-28	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; Reported with additional variants (phase unknown) in unrelated patients with polycystic kidney disease in published literature (Gunay-Aygun et al., 2010; Tong et al., 2016); This variant is associated with the following publications: (PMID: 19914852, 27752906)
Labcorp Genetics (formerly Invitae), Labcorp	RCV003502691	SCV004293749	pathogenic	Autosomal recessive polycystic kidney disease	2023-12-24	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 2210 of the PKHD1 protein (p.Gly2210Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal recessive polycystic kidney disease (PMID: 19914852). 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: 2412881). 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.