Submissions for variant NM_000297.4(PKD2):c.964C>T (p.Arg322Trp)

gnomAD frequency: 0.00001  dbSNP: rs1553925453

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000516923	SCV000614575	pathogenic	not provided	2022-12-30	criteria provided, single submitter	clinical testing	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. (25574838, 32332171)
Invitae	RCV000654890	SCV000776794	pathogenic	Autosomal dominant polycystic kidney disease	2022-11-08	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg322 amino acid residue in PKD2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15772804, 16540757, 23300259, 25574838). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects PKD2 function (PMID: 25574838). 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 PKD2 protein function. ClinVar contains an entry for this variant (Variation ID: 448039). This missense change has been observed in individuals with autosomal dominant polycystic kidney disease (PMID: 11968093, 15192819, 23300259; 17582161. 17100995). It has also been observed to segregate with disease in related individuals. This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 322 of the PKD2 protein (p.Arg322Trp).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001002478	SCV001160426	pathogenic	Polycystic kidney disease 2	2019-03-26	criteria provided, single submitter	clinical testing	The PKD2 c.964C>T; p.Arg322Trp variant is reported in several unrelated individuals with ADKPD (Chung 2006, Cornec-Le Gall 2017, Neumann 2013, Rossetti 2007) and shown to co-segregate with disease in a family (Reiterova 2002). This variant is classified as likely pathogenic/pathogenic in ClinVar (Variation ID: 448039). It is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 322 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Furthermore, other variants at this codon (Arg322Gln, Arg322Gly, Arg322Pro) have been associated with ADPKD (Audrezet 2016, Jin 2016, Neumann 2013, Robinson 2012, Rossetti 2012, Tan 2011, Trujillano 2014, Woerner 2006), suggesting this residue is critical for proper protein function. Based on available information, the p.Arg322Trp variant is considered to be pathogenic. REFERENCES Audrezet MP et al. Comprehensive PKD1 and PKD2 Mutation Analysis in Prenatal Autosomal Dominant Polycystic Kidney Disease. J Am Soc Nephrol. 2016 Mar;27(3):722-9. Chung W et al. PKD2 gene mutation analysis in Korean autosomal dominant polycystic kidney disease patients using two-dimensional gene scanning. Clin Genet. 2006 Dec;70(6):502-8. Cornec-Le Gall E et al. PKD2-Related Autosomal Dominant Polycystic Kidney Disease: Prevalence, Clinical Presentation, Mutation Spectrum, and Prognosis. Am J Kidney Dis. 2017 Oct;70(4):476-485. Jin M et al. System analysis of gene mutations and clinical phenotype in Chinese patients with autosomal-dominant polycystic kidney disease. Sci Rep. 2016 Oct 26;6:35945. Neumann HP et al. Epidemiology of autosomal-dominant polycystic kidney disease: an in-depth clinical study for south-western Germany. Nephrol Dial Transplant. 2013 Jun;28(6):1472-87. Reiterova J et al. Four novel mutations of the PKD2 gene in Czech families with autosomal dominant polycystic kidney disease. Hum Mutat. 2002 May;19(5):573. Robinson C et al. Clinical utility of PKD2 mutation testing in a polycystic kidney disease cohort attending a specialist nephrology out-patient clinic. BMC Nephrol. 2012 Aug 3;13:79 Rossetti S et al. Comprehensive molecular diagnostics in autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 2007 Jul;18(7):2143-60. Rossetti S et al. Identification of gene mutations in autosomal dominant polycystic kidney disease through targeted resequencing. J Am Soc Nephrol. 2012 May;23(5):915-33. Tan YC et al. Aberrant PKD2 splicing due to a presumed novel missense mutation in autosomal-dominant polycystic kidney disease. Clin Genet. 2011 Sep;80(3):287-92. Trujillano D et al. Diagnosis of autosomal dominant polycystic kidney disease using efficient PKD1 and PKD2 targeted next-generation sequencing. Mol Genet Genomic Med. 2014 Sep;2(5):412-21. Woerner AC et al. Tuberous sclerosis complex and polycystic kidney disease together: an exception to the contiguous gene syndrome. Genet Med. 2006 Mar;8(3):197-8.
Cavalleri Lab, Royal College of Surgeons in Ireland	RCV001002478	SCV001251265	likely pathogenic	Polycystic kidney disease 2	2020-02-05	criteria provided, single submitter	research	PM2, PM2, PP2, PP3, PP4, PP5
Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research	RCV000516923	SCV001422356	likely pathogenic	not provided	2019-01-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002525062	SCV003643589	pathogenic	Inborn genetic diseases	2022-10-13	criteria provided, single submitter	clinical testing	The c.964C>T (p.R322W) alteration is located in exon 4 (coding exon 4) of the PKD2 gene. This alteration results from a C to T substitution at nucleotide position 964, causing the arginine (R) at amino acid position 322 to be replaced by a tryptophan (W). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been observed in multiple individuals with a personal and/or family history of autosomal dominant polycystic kidney disease (Reiterová, 2002; Zhang, 2005; Rossetti, 2007; Neumann, 2013; Cornec-Le Gall, 2017; Benson, 2021; Mallawaarachchi, 2021; Kim, 2021; Yu, 2022). This amino acid position is highly conserved in available vertebrate species. Functional studies indicate this variant impairs channel gating without impacting channel cilia localization (Vien, 2020). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
GeneDx	RCV000516923	SCV003924709	pathogenic	not provided	2023-05-04	criteria provided, single submitter	clinical testing	Reported to segregate with disease in multiple affected individuals from a single family in published literature (Reiterova et al., 2002); however, limited information was provided on the family; Published functional studies suggest this variant disrupts normal complex formation (Gainullin et al., 2015); Not observed 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: 16767665, 25574838, 15192819, 11968093, 17100995, 23300259, 28356211, 17582161, 32332171, 33454723, 33437033, 34101167, 32816041, 35778421, 37028763)
PreventionGenetics, part of Exact Sciences	RCV003403222	SCV004119966	pathogenic	PKD2-related disorder	2023-06-02	criteria provided, single submitter	clinical testing	The PKD2 c.964C>T variant is predicted to result in the amino acid substitution p.Arg322Trp. This variant has been reported to segregate with autosomal dominant polycystic kidney disease (ADPKD) in a large Czech family (Reiterova et al. 2002. PubMed ID: 11968093). This variant has also been reported in several other unrelated patients with ADPKD (Chung et al. 2006. PubMed ID: 17100995; P15 in Kim et al. 2021. PubMed ID: 32816041; Supp. Table 3 in Benson et al. 2021. PubMed ID: 33454723). Different changes at the same codon have also been reported in ADPKD patients (p.Arg322Gly, Audrézet et al. 2016. PubMed ID: 26139440; p.Arg322Gln, Robinson et al. 2012. PubMed ID: 22863349 and Trujillano et al. 2014. PubMed ID: 25333066). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292058	SCV001480725	pathogenic	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD2 p.Arg322Trp variant was identified in 1 of 28 proband chromosomes (frequency: 0.04) from individuals or families with ADPKD of Czech ethnicity and was not identified in 100 control chromosomes from healthy individuals (Reiterova 2002,). The variant was also identified in the LOVD 3.0 database but no relevant information was given. The variant was not identified in dbSNP, ClinVar, ADPKD Mutation and PKD1-LOVD, databases. The variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, or the Exome Aggregation Consortium (August 8th 2016) nor the Genome Aggregation Consortium (Feb 27, 2017) control databases. The variant p.Arg322Trp in exon 4 causes a change from a positively charged arginine to a hydrophobic tryptophan in the first extracellular loop of the polycystin 2. In one study, this substitution segregated with the disease in a large family with six affected individuals. 50 unrelated individuals were tested and no similar change was observed (Reiterova 2002). The variant was also identified in a Chinese family with ADPKD (Zhang 2004). A different variant at the same position, where arginine is replaced with glutamine, was identified as disease causing and segregated with four individuals with ADPKD and one affected obligate carrier (Woerner 2006). In a letter to the editor, it is stated that a disease causing missense mutation p.Arg322Trp has been reported among PKD2- linked families of both Czech and Chinese ethnicities. The arginine at codon 322 of the PKD2 gene on chromosome 4q21-23 is remarkably conserved across species, indicating its importance this position. Indeed, as Reiterova et al. point out, this mutation variant occurs in a large extracellular loop of polycystin 2, and is likely to be necessary for proper folding of the protein, as well as interaction with other molecules (Reiterova 2002Woerner 2006). The p.Arg322 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the tryptophanTrp 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. The variant is located with the Polycystin cation channel of PKD2 Polycystic kidney disease type 2 protein functional domains increasing the likelihood that it may have clinical significance. In summary, this variant meets our laboratory’s criteria to be classified as pathogenic.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000516923	SCV002035475	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000516923	SCV002037518	pathogenic	not provided		no assertion criteria provided	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000516923	SCV003839868	pathogenic	not provided	2022-07-19	no assertion criteria provided	clinical testing	DNA sequence analysis of the PKD2 gene demonstrated a sequence change, c.964C>T, in exon 4 that results in an amino acid change, p.Arg322Trp. The p.Arg322Trp change affects a highly conserved amino acid residue located in the polycystin cation channel protein domain of the PKD2 protein that is known to be functional. The p.Arg322Trp substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change segregated with disease in six individuals from a family with autosomal dominant polycystic kidney disease (PMID: 11968093) and has also been observed in several other unrelated individuals affected with polycystic kidney disease (PMID: 15192819, 17100995, 17582161, 23300259, 28356211). Additionally, other sequence changes impacting the same amino acid residue (p.ARg322Gly, p.Arg322Gln) have been identified in individuals with polycystic kidney disease (PMID: 26139440, 15772804). This sequence change has not been described in population databases such as ExAC and gnomAD. Collectively, these evidences indicate this sequence change is pathogenic.