ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs1553926929
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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 RCV000517227 SCV000614567 pathogenic not provided 2022-12-29 criteria provided, single submitter clinical testing The frequency of this variant in the general population is consistent with pathogenicity ( This variant appears to segregate with disease in at least one family. Assessment of experimental evidence suggests this variant results in abnormal RNA splicing.
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.
GeneDx RCV000517227 SCV002558422 pathogenic not provided 2022-01-27 criteria provided, single submitter clinical testing RT-PCR of leukocyte mRNA revealed splice variants all terminating with premature stop codons (Wang et al., 2009); Intronic +5 splice site variant in a gene for which loss-of-function is a known mechanism of disease, and splice predictors support a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19158373, 17574468, 17582161)
Fulgent Genetics, Fulgent Genetics RCV001001334 SCV002810395 pathogenic Polycystic kidney disease 2 2022-01-07 criteria provided, single submitter clinical testing
Invitae RCV002527509 SCV003525506 pathogenic Autosomal dominant polycystic kidney disease 2023-07-19 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with altered splicing resulting in multiple RNA products (PMID: 19158373). ClinVar contains an entry for this variant (Variation ID: 448033). This variant is also known as IVS8+5 G>A. This variant has been observed in individual(s) with autosomal dominant polycystic kidney disease (PMID: 17574468, 17582161, 19158373). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 8 of the PKD2 gene. It does not directly change the encoded amino acid sequence of the PKD2 protein. It affects a nucleotide within the consensus splice site.
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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