ClinVar Genomic variation as it relates to human health

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.

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.

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)

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.

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with polycystic kidney disease 2 (MIM#613095). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Variant summary: PKD2 c.1081C>T (p.Arg361X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251092 control chromosomes. c.1081C>T has been reported in the literature in multiple individuals affected with Polycystic Kidney Disease 2 (e.g. Cornec-Le Gall_2017). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 28356211). ClinVar contains an entry for this variant (Variation ID: 636770). Based on the evidence outlined above, the variant was classified as pathogenic.

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.

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.

The PKD2 c.1081C>T variant is predicted to result in premature protein termination (p.Arg361*). This variant has been reported in many individuals with polycystic kidney disease (Chung et al. 2006. PubMed ID: 17100995; Paavola et al. 2013. PubMed ID: 23376035; Kim et al. 2019. PubMed ID: 31740684; Moriyama et al. 2020. PubMed ID: 33141305; Durkie et al. 2020. PubMed ID: 33168999). This variant has not been reported in a large population database, indicating this variant is rare. This variant has been reported in ClinVar by many outside laboratories as pathogenic (ncbi.nlm.nih.gov/clinvar/variation/636770). Nonsense variants in PKD2 are expected to be pathogenic. This variant is interpreted as pathogenic.