Submissions for variant NM_138694.4(PKHD1):c.8407T>C (p.Cys2803Arg)

gnomAD frequency: 0.00011  dbSNP: rs398124495

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000790666	SCV000231334	likely pathogenic	not provided	2015-08-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174653	SCV001337868	uncertain significance	not specified	2020-01-30	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.8407T>C (p.Cys2803Arg) 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 2e-05 in 251274 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8407T>C has been reported in the literature in two individuals affected with Polycystic Kidney and Hepatic Disease; one individual carried the variant and another variant of unknown significance (Gunay-Aygun_2010) while another individual carried the variant along with two other putative pathogenic variants (phase unknown) (Tong_2016). These reports do not allow unequivocal conclusions about association of the variant with Polycystic Kidney and Hepatic Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance until additional evidence of clinical and functional importance becomes available.
Invitae	RCV000179135	SCV001417096	pathogenic	Autosomal recessive polycystic kidney disease	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 2803 of the PKHD1 protein (p.Cys2803Arg). This variant is present in population databases (rs398124495, gnomAD 0.007%). This missense change has been observed in individual(s) with polycystic kidney disease (PMID: 19914852, 33532864). 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: 96432). 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.
Molecular Biology Laboratory, Fundació Puigvert	RCV000179135	SCV001425239	pathogenic	Autosomal recessive polycystic kidney disease	2020-02-01	criteria provided, single submitter	research
GeneDx	RCV000790666	SCV002061143	likely pathogenic	not provided	2022-01-07	criteria provided, single submitter	clinical testing	Identified in in multiple patients with autosomal recessive polycystic kidney disease along with another PKHD1 variant in unknown phase (Gunay-Aygun et al., 2010; Tong et al., 2016); Not observed at a 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: 20413436, 19914852, 27752906, 30510609)
PreventionGenetics, part of Exact Sciences	RCV003407467	SCV004115686	likely pathogenic	PKHD1-related disorder	2023-08-05	criteria provided, single submitter	clinical testing	The PKHD1 c.8407T>C variant is predicted to result in the amino acid substitution p.Cys2803Arg. This variant was reported in individuals with autosomal recessive polycystic kidney disease (ARPKD; Gunay-Aygun et al. 2010. PubMed ID: 19914852; Gunay-Aygun et al. 2010. PubMed ID: 20413436; Tong et al. 2016. PubMed ID: 27752906; Rivas et al. 2019. PubMed ID: 30510609). At PreventionGenetics, this variant was identified along with different pathogenic PKHD1 variants in multiple individuals with ARPKD. This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/6-51656067-A-G). This variant is interpreted as likely pathogenic.
Counsyl	RCV000179135	SCV000487153	likely pathogenic	Autosomal recessive polycystic kidney disease	2016-10-12	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000179135	SCV002077979	uncertain significance	Autosomal recessive polycystic kidney disease	2017-07-28	no assertion criteria provided	clinical testing