Submissions for variant NM_138694.4(PKHD1):c.1980C>G (p.Cys660Trp)

dbSNP: rs1554214097

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	RCV000590035	SCV000699853	uncertain significance	not provided	2016-08-09	criteria provided, single submitter	clinical testing	Variant summary: The PKHD1 c.1980C>G (p.Cys660Trp) variant involves the alteration of a non-conserved nucleotide. 3/3 in silico tools predict a damaging outcome for this variant (MutationTaster not captured due to low reliability index). This variant is not located in any known domain (InterPro). This variant is absent in 120606 control chromosomes. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories, nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae	RCV001834859	SCV004275344	likely pathogenic	Autosomal recessive polycystic kidney disease	2023-12-16	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 660 of the PKHD1 protein (p.Cys660Trp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PKHD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 496516). 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%. This variant disrupts the p.Cys660 amino acid residue in PKHD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Natera, Inc.	RCV001834859	SCV002081050	uncertain significance	Autosomal recessive polycystic kidney disease	2018-11-25	no assertion criteria provided	clinical testing