ClinVar Miner

Submissions for variant NM_000297.4(PKD2):c.964C>T (p.Arg322Trp) (rs1553925453)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000516923 SCV000614575 likely pathogenic not provided 2016-07-26 criteria provided, single submitter clinical testing
Invitae RCV000654890 SCV000776794 pathogenic Autosomal dominant polycystic kidney disease 2017-10-12 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 322 of the PKD2 protein (p.Arg322Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with dominant polycystic kidney disease in a family (PMID: 11968093), and has also been observed in several other unrelated individuals affected with the disease (PMID: 15192819, 17100995, 17582161, 23300259, 28356211). Experimental studies, in vitro, have shown that this missense change disrupts polycystin-1 glycosylation (PMID: 25574838). A different missense substitution at this codon (p.Arg322Gln) has been determined to be pathogenic (PMID: 15772804, 16540757, 23300259, 25574838). This suggests that the arginine residue is critical for PKD2 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
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
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.

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