Submissions for variant NM_138694.4(PKHD1):c.10444C>T (p.Arg3482Cys)

gnomAD frequency: 0.00002  dbSNP: rs148617572

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169255	SCV000220543	likely pathogenic	Autosomal recessive polycystic kidney disease	2014-07-23	criteria provided, single submitter	literature only
Eurofins Ntd Llc (ga)	RCV000726420	SCV000344513	pathogenic	not provided	2016-08-05	criteria provided, single submitter	clinical testing
Invitae	RCV000169255	SCV000754646	pathogenic	Autosomal recessive polycystic kidney disease	2024-01-27	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 3482 of the PKHD1 protein (p.Arg3482Cys). This variant is present in population databases (rs148617572, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive polycystic kidney disease and related conditions (PMID: 12506140, 15108281, 15805161, 26385851, 26721323). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 188896). 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.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000169255	SCV000965800	likely pathogenic	Autosomal recessive polycystic kidney disease	2014-01-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000169255	SCV001163015	pathogenic	Autosomal recessive polycystic kidney disease		criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001331692	SCV001523788	pathogenic	Polycystic kidney disease 4	2019-11-07	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx	RCV000726420	SCV001805444	pathogenic	not provided	2023-09-21	criteria provided, single submitter	clinical testing	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: 26721323, 12506140, 15108277, 15698423, 19914852, 26385851, 25114813, 15805161, 19940839, 34426522, 33940108, 15108281, 30275481, 37013475, 35812281, Corradi2022[abstract], 36964991)
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV001331692	SCV003807434	pathogenic	Polycystic kidney disease 4	2022-07-22	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS4 strong, PM2 moderated, PM3 moderated, PP1 supporting
PreventionGenetics, part of Exact Sciences	RCV003937523	SCV004747648	pathogenic	PKHD1-related disorder	2023-11-17	criteria provided, single submitter	clinical testing	The PKHD1 c.10444C>T variant is predicted to result in the amino acid substitution p.Arg3482Cys. This variant has been repeatedly reported to be pathogenic for autosomal recessive polycystic kidney disease (ARPKD) (see for example, Bergmann et al. 2003. PubMed ID: 12506140; Thakur et al. 2014. PubMed ID: 25114813; Quint et al. 2015. PubMed ID: 26721323). This variant is reported in 0.023% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/6-51524480-G-A). This variant is interpreted as pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV001331692	SCV005042824	pathogenic	Polycystic kidney disease 4		criteria provided, single submitter	clinical testing	The missense c.10444C>Tp.Arg3482Cys variant in PKHD1 gene has been reported previously in homozygous or compound heterozygous state in individuals affected with Autosomal recessive polycystic kidney disease ARPKD Quint A et al., 2016. This variant is reported with the allele frequency of 0.006% in the gnomAD Exomes and novel in 1000 Genomes. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic multiple submitters. The amino acid Arg at position 3482 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg3482Cys in PKHD1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. 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 indicates that this missense variant is expected to disrupt PKHD1 protein function. The variant is predicted as damaging by SIFT. For these reasons, this variant has been classified as Pathogenic.