Submissions for variant NM_138694.4(PKHD1):c.7717C>T (p.Arg2573Cys)

gnomAD frequency: 0.00001  dbSNP: rs752994816

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000592239	SCV000705484	uncertain significance	not provided	2017-02-09	criteria provided, single submitter	clinical testing
Invitae	RCV000668244	SCV000815446	pathogenic	Autosomal recessive polycystic kidney disease	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2573 of the PKHD1 protein (p.Arg2573Cys). This variant is present in population databases (rs752994816, gnomAD 0.005%). This missense change has been observed in individual(s) with autosomal recessive polycystic kidney disease (PMID: 27225849, 28578020). 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: 499806). 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%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV000592239	SCV000927444	likely pathogenic	not provided	2017-10-19	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001810463	SCV002060194	likely pathogenic	Polycystic kidney disease 4	2021-11-11	criteria provided, single submitter	clinical testing	NM_138694.3(PKHD1):c.7717C>T(R2573C) is a missense variant classified as likely pathogenic in the context of autosomal recessive polycystic kidney disease, PKHD1-related. R2573C has been observed in cases with relevant disease (PMID: 27225849, 28578020, 27752906, 19914852, 31738409, 33123899). Functional assessments of this variant are not available in the literature. R2573C has been observed in population frequency databases (gnomAD: EAS 0.01%). In summary, NM_138694.3(PKHD1):c.7717C>T(R2573C) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Baylor Genetics	RCV001810463	SCV004204545	likely pathogenic	Polycystic kidney disease 4	2023-09-14	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000668244	SCV001459184	uncertain significance	Autosomal recessive polycystic kidney disease	2020-09-16	no assertion criteria provided	clinical testing
Laboratory of Gastroenterology and Hepatology, Radboud University Medical Center	RCV001844840	SCV001876974	uncertain significance	Autosomal dominant polycystic liver disease	2021-09-01	no assertion criteria provided	research