ClinVar Miner

Submissions for variant NM_004562.3(PRKN):c.98G>A (p.Arg33Gln)

gnomAD frequency: 0.00006  dbSNP: rs147757966
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Center for Human Genetics Tuebingen RCV001090784 SCV001246506 pathogenic not provided 2019-05-01 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001090784 SCV001584588 pathogenic not provided 2024-01-17 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 33 of the PRKN protein (p.Arg33Gln). This variant is present in population databases (rs147757966, gnomAD 0.02%). This missense change has been observed in individuals with early-onset Parkinson disease (PMID: 12730996, 16643317, 19636047). It has also been observed to segregate with disease in related individuals. This variant is also known as 199G>A. ClinVar contains an entry for this variant (Variation ID: 578186). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects PRKN function (PMID: 15606901, 21348451, 21694720, 23770917, 24647965, 26631732, 27534820). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV005004377 SCV001652808 pathogenic Autosomal recessive juvenile Parkinson disease 2; Ovarian cancer; Lung cancer 2024-04-20 criteria provided, single submitter clinical testing
AiLife Diagnostics, AiLife Diagnostics RCV001090784 SCV002502335 likely pathogenic not provided 2021-09-10 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003907954 SCV004721558 pathogenic PRKN-related disorder 2024-02-29 no assertion criteria provided clinical testing The PRKN c.98G>A variant is predicted to result in the amino acid substitution p.Arg33Gln. This variant has been reported in the compound heterozygous state in individuals with both early- and late-onset Parkinson disease (Oliveira et al. 2003. PubMed ID: 12730996; Table e-1, Pankratz et al. 2009. PubMed ID: 19636047). Functional studies have shown that the p.Arg33Gln variant leads to lower steady-state levels of the PRKN protein (Henn et al. 2005. PubMed ID: 15606901) and reduce the ability of the Ubl domain of PRKN to become phosphorylated (Aguirre et al. 2018. PubMed ID: 29530980). Additional functional studies support the findings that the c.98G>A (p.Arg33Gln) variant impairs the function and stability of the PRKN protein (Chaugule et al. 2011. PubMed ID: 21694720; Safadi et al. 2011. PubMed ID: 21348451).This variant is reported in 0.016% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Based on this evidence, this variant is interpreted as pathogenic.

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