Submissions for variant NM_138694.4(PKHD1):c.8870T>C (p.Ile2957Thr)

gnomAD frequency: 0.00007  dbSNP: rs760222236

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000390646	SCV000464050	pathogenic	Autosomal recessive polycystic kidney disease	2017-04-27	criteria provided, single submitter	clinical testing	Across nine studies, the PKHD1 c.8870T>C (p.Ile2957Thr) missense variant is reported in a total of 23 patients, including 19 compound heterozygotes with autosomal recessive polycystic kidney disease (ARPKD), one compound heterozygote with Caroli's disease and congenital hepatic fibrosis with minimal kidney involvement, two ARPKD patients carrying three variants in the PKHD1 gene, and one heterozygote in whom a second variant was not identified (Onuchic et al. 2002; Ward et al. 2002; Bergmann et al. 2003; Rossetti et al. 2003; Sharp et al. 2005; Gunay-Aygun et al. 2010; Denamur et al. 2010; Brinkert et al. 2013; Melchionda et al. 2016). Additionally, the p.Ile2957Thr variant was found in a heterozygous state in three unaffected family members of patients, and is noted to segregate in a manner consistent with recessive inheritance. The variant was absent from 360 control individuals and from at least 300 control chromosomes, but is reported at a frequency of 0.00013 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence, the p.Ile2957Thr variant is classified as pathogenic for autosomal recessive polycystic kidney disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
GeneDx	RCV000521323	SCV000617329	pathogenic	not provided	2023-05-02	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; This variant is associated with the following publications: (PMID: 20413436, 12846734, 19914852, 12874454, 15805161, 25701400, 15108281, 12506140, 27225849, 26385851, 11919560, 11898128, 19940839, 31980526, 32571524, 32574212, 31589614, 32939031)
Invitae	RCV000390646	SCV000629936	pathogenic	Autosomal recessive polycystic kidney disease	2023-12-14	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2957 of the PKHD1 protein (p.Ile2957Thr). This variant is present in population databases (rs760222236, gnomAD 0.01%). This missense change has been observed in individual(s) with polycystic kidney disease (PMID: 11898128, 11919560, 12506140, 15698423, 15805161, 19914852, 27225849). 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: 357423). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000390646	SCV000699885	pathogenic	Autosomal recessive polycystic kidney disease	2017-01-23	criteria provided, single submitter	clinical testing	Variant summary: The PKHD1 c.8870T>C (p.Ile2957Thr) variant involves the alteration of a conserved nucleotide, which 3/4 in silico tools predict damaging outcome for this variant. This variant was found in 10/122220 control chromosomes at a frequency of 0.0000818, which does not exceed the estimated maximal expected allele frequency of a pathogenic PKHD1 variant (0.0070711). In literature, this variant is widely reported as a pathogenic variant and is found in several patients with autosomal recessive polycystic kidney disease with consistent genotype-phenotype evidences. Available patient data show that this variant is a severe mutation. A patient who carried 10627delT and p.I2957T variants was found to have no ARPKD protein (i.e. fibronectin), strongly suggesting that this variant leads to functional impairment (Ward_2003). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.
Baylor Genetics	RCV000390646	SCV001163022	pathogenic	Autosomal recessive polycystic kidney disease		criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000390646	SCV001427105	pathogenic	Autosomal recessive polycystic kidney disease	2018-05-14	criteria provided, single submitter	clinical testing	A heterozygous missense variant, NM_138694.3(PKHD1):c.8870T>C, has been identified in exon 57 of 67 in the PKHD1 gene. The variant is predicted to result in a moderate amino acid change from an isoleucine to a threonine at position 2957 of the protein, NP_619639.3(PKHD1):p.(Ile2957Thr). The isoleucine residue at this position has moderate conservation (100 vertebrates, UCSC), but is not located within a well established functional domain. In silico predictions of pathogenicity for this variant are conflicting (Polyphen, SIFT, CADD, Mutation Taster) and the variant is present in the gnomAD database at a frequency of 0.0058% (16 heterozygotes, 0 homozygotes). However, the variant has been previously described as pathogenic in multiple individuals with autosomal recessive polycystic kidney disease (ClinVar, Ward et al., (2003)). Additionally, functional analysis compared fibrocystin in normal controls and a compound heterozygous patient (p.(Ile2957Thr) and a truncating variant). No fibrocystin was detected in the kidneys of this patient, suggesting a loss of protein function (Ward et al., (2003)). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.
Fulgent Genetics, Fulgent Genetics	RCV002502379	SCV002811579	pathogenic	Polycystic kidney disease 4	2022-05-11	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003409556	SCV004106128	pathogenic	PKHD1-related disorder	2024-02-02	criteria provided, single submitter	clinical testing	The PKHD1 c.8870T>C variant is predicted to result in the amino acid substitution p.Ile2957Thr. This variant has been widely reported to be pathogenic for autosomal recessive polycystic kidney disease (ARPKD) (see for example, Ward et al. 2002. PubMed ID: 11919560; Obeidova et al. 2020. PubMed ID: 32574212; Table S2, Jayasinghe et al. 2021. PubMed ID: 32939031). This variant is reported in 0.010% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.
Baylor Genetics	RCV002502379	SCV004202200	pathogenic	Polycystic kidney disease 4	2023-10-31	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292483	SCV001480591	pathogenic	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKHD1 p.Ile2957Thr variant was identified in 15 of 690 proband chromosomes (frequency: 0.02) from individuals or families with ARPKD or congenital hepatic fibrosis and was not identified in 520 chromosomes from healthy individuals (Adeva 2006, Denamur 2010, Furu 2003, Gunay-Aygun 2010, Sharp 2005, Ward 2002). The variant was also identified in dbSNP (ID: rs760222236) “With Pathogenic allele”, ClinVar (classified pathogenic by Illumina Clinical Services Laboratory), RWTH AAachen University ARPKD database (classified pathogenic). The variant was also identified in control databases in 16 of 276840 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 1 of 24028 chromosomes (freq: 0.00004), European Non-Finnish in 14 of 126434 chromosomes (freq: 0.0001), and South Asian in 1 of 30782 chromosomes (freq: 0.00003); it was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, or European Finnish populations. The p.Ile2957 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Thr variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.
Natera, Inc.	RCV000390646	SCV002077963	pathogenic	Autosomal recessive polycystic kidney disease	2017-03-17	no assertion criteria provided	clinical testing