ClinVar Miner

Submissions for variant NM_000311.5(PRNP):c.598G>A (p.Glu200Lys) (rs28933385)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000644587 SCV000766287 pathogenic Huntington disease-like 1 2018-11-27 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 200 of the PRNP protein (p.Glu200Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant is the most common variant reported world-wide in individuals and families affected with Creutzfeldt-Jakob disease (CJD) (PMID: 2572450, 20514992, 10360778, 23296137, 20593190, 25064618, 15366237, 22584955, 11839833, 25522698, 14967768, 27803826). This variant is highly penetrant, and carriers have a near 100% lifetime risk of developing prion disease (PMID: 26791950). ClinVar contains an entry for this variant (Variation ID: 13398). Experimental studies have shown that this missense change leads to functional and structural changes in the PRNP protein (PMID: 20139714, 23723004, 22318125, 9813003, 23132868, 21298055, 17494694). In addition, mice with a chimeric human–mouse PRNP transgene that were inoculated with brain extract from affected individuals carrying this variant developed prion disease (PMID: 11756597). Finally, transgenic mice expressing the p.Glu200Lys (E200K) protein develop neurodegenerative disease pathology consistent with human prion disease (PMID: 22072968). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000014334 SCV000034583 pathogenic Jakob-Creutzfeldt disease 2014-10-02 no assertion criteria provided literature only
OMIM RCV000014335 SCV000034584 pathogenic Fatal familial insomnia 2014-10-02 no assertion criteria provided literature only
GeneReviews RCV000020253 SCV000040607 pathologic Genetic prion diseases 2008-12-18 no assertion criteria provided curation Converted during submission to Pathogenic.

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