ClinVar Miner

Submissions for variant NM_000297.4(PKD2):c.1081C>T (p.Arg361Ter)

gnomAD frequency: 0.00001  dbSNP: rs1578130676
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000788690 SCV000927887 pathogenic not provided 2018-08-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001000981 SCV001158083 pathogenic Polycystic kidney disease 2 2018-12-30 criteria provided, single submitter clinical testing The PKD2 c.1081C>T; p.Arg361Ter variant has been described in multiple individuals affected with autosomal dominant polycystic kidney disease (ADPKD; see link to Mayo ADPKD database, Chung 2006, Jin 2016, Paavola 2013, Robinson 2012). It is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered pathogenic. REFERENCES Link to Mayo ADPKD database: http://pkdb.mayo.edu/cgi-bin/v2_display_mutations.cgi?GENE=PKD2&apkd_mode=PROD 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. 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. Paavola J et al. Polycystin-2 mutations lead to impaired calcium cycling in the heart and predispose to dilated cardiomyopathy. J Mol Cell Cardiol. 2013 May;58:199-208. 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; 13: 79.
CeGaT Center for Human Genetics Tuebingen RCV000788690 SCV001250327 pathogenic not provided 2019-04-01 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV001000981 SCV001752522 pathogenic Polycystic kidney disease 2 2022-04-08 criteria provided, single submitter clinical testing
GeneDx RCV000788690 SCV001782674 pathogenic not provided 2023-09-01 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30215095, 27782177, 30816285, 23376035, 25525159, 17100995, 22508176, 22863349, 31740684, 33168999, 33726816, 34101167, 33141305, 35478332)
Invitae RCV001869209 SCV002133882 pathogenic Autosomal dominant polycystic kidney disease 2023-10-12 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg361*) in the PKD2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PKD2 are known to be pathogenic (PMID: 17582161, 22863349). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with autosomal dominant polycystic kidney disease type 2 (PMID: 23376035, 31740684). ClinVar contains an entry for this variant (Variation ID: 636770). For these reasons, this variant has been classified as Pathogenic.
Lifecell International Pvt. Ltd RCV001000981 SCV003925694 likely pathogenic Polycystic kidney disease 2 criteria provided, single submitter clinical testing A Heterozygous Nonsense variant c.1081C>T in Exon 4 of the PKD2 gene that results in the amino acid substitution p.Arg361* was identified. The observed variant is novel in gnomAD exomes and genomes. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic [Variation ID:636770]. For these reasons, this variant has been classified as Likely Pathogenic.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center RCV001000981 SCV004808127 pathogenic Polycystic kidney disease 2 2024-03-29 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001292537 SCV001480746 pathogenic Polycystic kidney disease no assertion criteria provided clinical testing The PKD2 p.Arg361* variant was identified in 8 of 2162 proband chromosomes (frequency: 0.004) from individuals or families with autosomal dominant polycystic kidney disease (Audrezet 2012, Chung 2006, Jin 2016, Robinson 2012). The variant was also identified in LOVD 3.0 (1x) and the ADPKD Mutation Database (as definitely pathogenic). The variant was not identified in dbSNP, ClinVar, or PKD1-LOVD. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The p.Arg361* variant leads to a premature stop codon at position 361, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the PKD2 gene are an established mechanism of disease in ADPKD and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Genetic Services Laboratory, University of Chicago RCV000788690 SCV003839866 pathogenic not provided 2022-09-02 no assertion criteria provided clinical testing DNA sequence analysis of the PKD2 gene demonstrated a sequence change, c.1081C>T, which results in the creation of a premature stop codon at amino acid position 361, p.Arg361*. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated PKD2 protein with potentially abnormal function. This sequence change has not been described in population databases such as ExAC and gnomAD. This pathogenic sequence change has previously been described in multiple individuals with autosomal dominant polycystic kidney disease (PMID: 34101167, 30816285, 33141305, 31740684, 27782177, 17100995, 22508176). Based on these collective evidences, this sequence change is classified as pathogenic.

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