ClinVar Miner

Submissions for variant NM_000297.4(PKD2):c.1898+5G>A (rs1553926929)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000517227 SCV000614567 pathogenic not provided 2017-07-21 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001001334 SCV001158524 likely pathogenic Polycystic kidney disease 2 2019-05-24 criteria provided, single submitter clinical testing The PKD2 c.1898+5G>A variant is reported in the literature in multiple individuals affected with autosomal dominant polycystic kidney disease (Garcia-Gonzalez 2007, Rossetti 2007, Wang 2009). This variant is reported in ClinVar (Variation ID: 448033), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This is an intronic variant in a highly conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by significantly weakening the nearby canonical donor splice site. Additionally, functional analyses from patient samples demonstrate aberrant transcripts predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay (Wang 2009). Based on available information, this variant is considered to be likely pathogenic. References: Garcia-Gonzalez MA et al. Evaluating the clinical utility of a molecular genetic test for polycystic kidney disease. Mol Genet Metab. 2007 Sep-Oct;92(1-2):160-7. Rossetti S et al. Comprehensive molecular diagnostics in autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 2007 Jul;18(7):2143-60. Wang K et al. Evidence for pathogenicity of atypical splice mutations in autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol. 2009 Feb;4(2):442-9.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001292443 SCV001480939 likely pathogenic Polycystic kidney disease no assertion criteria provided clinical testing The PKD2 c.1898+5G>A variant was identified in 1 of 164 proband chromosomes (frequency: 0.006) from individuals or families with ADPKD and was not identified in 342 control chromosomes from healthy individual. The PKD2: IVS8+5G>A occurred at the 5th base pair of the splice-donor site, which is highly conserved. This variant was predicted to result in improper splicing by both the ASSA and SSPNN programs (Garcia-Gonzalez 2007). The variant was also identified in LOVD 3.0 database but no clinical information was provided; and in ADPKD Mutation Database 4X as Highly Likely Pathogenic with an amino acid frameshift prediction (p.Leu573fs) as a result of as splice defect. The variant was not identified in dbSNP, ClinVar, GeneInsight-COGR, or PKD1-LOVD, databases. Furthermore, the variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. The c.1898+5G>A variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing 4bp upstream at the consensus splice site location. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.

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