ClinVar Miner

Submissions for variant NM_000297.4(PKD2):c.974G>A (p.Arg325Gln)

dbSNP: rs1727420867
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cavalleri Lab, Royal College of Surgeons in Ireland RCV001095617 SCV001251254 likely pathogenic Polycystic kidney disease 2 2020-02-05 criteria provided, single submitter research PM2, PP2, PP3, PP4, PP5
Fulgent Genetics, Fulgent Genetics RCV001095617 SCV002812938 pathogenic Polycystic kidney disease 2 2022-02-19 criteria provided, single submitter clinical testing
Ambry Genetics RCV002554878 SCV003598714 likely pathogenic Inborn genetic diseases 2021-12-28 criteria provided, single submitter clinical testing The c.974G>A (p.R325Q) alteration is located in exon 4 (coding exon 4) of the PKD2 gene. This alteration results from a G to A substitution at nucleotide position 974, causing the arginine (R) at amino acid position 325 to be replaced by a glutamine (Q). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been identified in several families with autosomal dominant polycystic kidney disease (Rossetti, 2007; Cornec-Le Gall, 2017; Kim, 2019; Mantovani, 2020). Based on the available evidence, this alteration is classified as likely pathogenic.
GeneDx RCV003151832 SCV003840618 likely pathogenic not provided 2023-03-07 criteria provided, single submitter clinical testing Published functional studies suggest p.(R325Q) leads to loss of ciliary current and shift of voltage-dependent channel opening (Vien et al., 2020); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 20950398, 31740684, 22008521, 36763973, 32457805, 33454723, 28356211, 17582161, 32332171)
PreventionGenetics, part of Exact Sciences RCV003405299 SCV004107639 pathogenic PKD2-related disorder 2023-09-27 criteria provided, single submitter clinical testing The PKD2 c.974G>A variant is predicted to result in the amino acid substitution p.Arg325Gln. This variant has not been reported in a large population database (, indicating this variant is rare. This variant has been reported to segregate with autosomal dominant polycystic kidney disease (ADPKD) in a family and was classified as a “highly likely pathogenic” variant (Rossetti et al. 2007. PubMed ID: 17582161). Later, it was repeatedly reported in other presumably unrelated individuals with polycystic kidney disease (Bataille et al. 2011. PubMed ID: 22008521; Kim et al. 2019. PubMed ID: 31740684, supplementary tables; Vien et al. 2020. PubMed ID: 32332171; Benson et al. 2021. PubMed ID: 33454723, Suppl. Table 3). The Vien et al. study suggested that variants located within the TOP domain of polycystin-2 (encoded by PKD2), including this variant, result in failure to open the channels at normal voltages although the channels can be normally assembled. Of note, we have found this variant in the heterozygous state in presumably unrelated patients tested for polycystic kidney disease at PreventionGenetics. Taken together, this variant is interpreted as pathogenic.

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