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

dbSNP: rs28933385

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000644587	SCV000766287	pathogenic	Huntington disease-like 1	2024-01-01	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 200 of the PRNP protein (p.Glu200Lys). This variant is present in population databases (rs28933385, gnomAD 0.003%). This missense change has been observed in individuals with Creutzfeldt-Jakob disease (CJD) (PMID: 2572450, 10360778, 11839833, 14967768, 15366237, 20514992, 20593190, 22584955, 23296137, 25064618, 25522698, 27803826). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13398). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PRNP protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PRNP function (PMID: 9813003, 11756597, 17494694, 20139714, 21298055, 22072968, 22318125, 23132868, 23723004). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001310451	SCV001471955	pathogenic	not provided	2020-06-11	criteria provided, single submitter	clinical testing	The PRNP c.598G>A; p.Glu200Lys variant (rs28933385) is one of a limited-number of missense variants in PRNP definitively associated with familial Creutzfeldt-Jakob disease (fCJD) and is the identified in over 70% of fCJD cases worldwide (Lee 1999, Colombo 2000). First described in 1989, this variant was found to underlie the relatively high incidence of fCJD in individuals of Sephardic Jewish/Iberian ancestry; although it has been observed in other populations (selected references: Goldgaber 1989, Goldfarb 1991, Meiner 1997, Lee 1999). This variant is present on a single Latino chromosome in the Genome Aggregation Database, and is often be inherited from an asymptomatic parent. However, while the penetrance of this allele is age-dependent, it reaches 100% by age 80 (Minikel 2016). The precise molecular nature of how this variant imparts pathogenicity is not fully understood; nonetheless, functional studies have demonstrated that transgenic expression of the p.Glu200Lys variant in mice leads to the development of neurological and histological features of CJD similar to human patients (Friedman-Levi 2011). Based on these observations, this variant is considered pathogenic with age-dependent penetrance. References: Goldgaber D et al. Mutations in familial Creutzfeldt-Jakob disease and Gerstmann-Sträussler-Scheinker's syndrome. Exp Neurol. 1989 Nov;106(2):204-6. Goldfarb LG et al. Creutzfeldt-Jacob disease associated with the PRNP codon 200Lys mutation: an analysis of 45 families. Eur J Epidemiol. 1991 Sep;7(5):477-86. Lee HS et al. Ancestral origins and worldwide distribution of the PRNP 200K mutation causing familial Creutzfeldt-Jakob disease. Am J Hum Genet. 1999 Apr;64(4):1063-70. Colombo R. Age and origin of the PRNP E200K mutation causing familial Creutzfeldt-Jacob disease in Libyan Jews. Am J Hum Genet. 2000 Aug;67(2):528-31. Meiner Z et al. Familial Creutzfeldt-Jakob disease. Codon 200 prion disease in Libyan Jews. Medicine (Baltimore). 1997 Jul;76(4):227-37. Minikel EV et al. Quantifying prion disease penetrance using large population control cohorts. Sci Transl Med. 2016 Jan 20;8(322):322ra9. Friedman-Levi Y et al. Fatal prion disease in a mouse model of genetic E200K Creutzfeldt-Jakob disease. PLoS Pathog. 2011 Nov;7(11):e1002350.
CeGaT Center for Human Genetics Tuebingen	RCV001310451	SCV001500251	pathogenic	not provided	2020-11-01	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV001310451	SCV001715306	pathogenic	not provided	2019-05-06	criteria provided, single submitter	clinical testing	PS3, PM2, PS4_moderate, PP4, PP5
GeneDx	RCV001310451	SCV001822987	pathogenic	not provided	2021-05-26	criteria provided, single submitter	clinical testing	Published functional studies demonstrate the variant results in PrP aggregates in brain extracts from transgeneic mice carrying this variant (Friedman-Levi et al., 2011); Mice that were inoculated with brain extract from affected individuals carrying this variant developed prion disease (Tateishi et al., 1996); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 15459517, 32367297, 9864731, 25279981, 31965421, 31589614, 1684755, 8614527, 30817871, 30755683, 30369528, 30369525, 17285519, 12197632, 19597763, 10090891, 18176009, 19822779, 8780103, 11839833, 27803826, 26791950, 11756597, 14967768, 23296137, 15366237, 20139714, 22912570, 22072968, 19543376, 23555862, 21298055, 21552571, 20730466, 8618678, 23966072, 22318125, 21689662, 9813003, 23132868, 14761942, 17494694, 25522698, 22584955, 21094273, 25064618, 23723004, 25149502, 10079068, 20514992, 10360778, 20593190, 2572450)
Revvity Omics, Revvity	RCV001310451	SCV002019522	pathogenic	not provided	2023-10-13	criteria provided, single submitter	clinical testing
OMIM	RCV000014334	SCV000034583	pathogenic	Inherited Creutzfeldt-Jakob 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	RCV000014334	SCV000040607	not provided	Inherited Creutzfeldt-Jakob disease		no assertion provided	literature only	Associated with genetic Creutzfeldt-Jakob disease phenotype. One of the five most common variants that account for 85% of genetic prion disease.