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rs28933385

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PP3_StrongPP5_Very_Strong

The NM_000311.5(PRNP):c.598G>A(p.Glu200Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000889 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

PRNP
NM_000311.5 missense

Scores

9
6
3

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8O:1

Conservation

PhyloP100: 4.33
Variant links:
Genes affected
PRNP (HGNC:9449): (prion protein (Kanno blood group)) The protein encoded by this gene is a membrane glycosylphosphatidylinositol-anchored glycoprotein that tends to aggregate into rod-like structures. The encoded protein contains a highly unstable region of five tandem octapeptide repeats. This gene is found on chromosome 20, approximately 20 kbp upstream of a gene which encodes a biochemically and structurally similar protein to the one encoded by this gene. Mutations in the repeat region as well as elsewhere in this gene have been associated with Creutzfeldt-Jakob disease, fatal familial insomnia, Gerstmann-Straussler disease, Huntington disease-like 1, and kuru. An overlapping open reading frame has been found for this gene that encodes a smaller, structurally unrelated protein, AltPrp. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2014]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000311.5
PP3
MetaRNN computational evidence supports a deleterious effect, 0.957
PP5
Variant 20-4699818-G-A is Pathogenic according to our data. Variant chr20-4699818-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 13398.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-4699818-G-A is described in Lovd as [Pathogenic]. Variant chr20-4699818-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PRNPNM_000311.5 linkuse as main transcriptc.598G>A p.Glu200Lys missense_variant 2/2 ENST00000379440.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PRNPENST00000379440.9 linkuse as main transcriptc.598G>A p.Glu200Lys missense_variant 2/21 NM_000311.5 P1P04156-1
PRNPENST00000424424.2 linkuse as main transcriptc.598G>A p.Glu200Lys missense_variant 2/21 P1P04156-1
PRNPENST00000430350.2 linkuse as main transcriptc.598G>A p.Glu200Lys missense_variant 2/21 P1P04156-1
PRNPENST00000457586.2 linkuse as main transcriptc.598G>A p.Glu200Lys missense_variant 2/21 P1P04156-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251466
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135906
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000889
AC:
13
AN:
1461878
Hom.:
0
Cov.:
32
AF XY:
0.00000825
AC XY:
6
AN XY:
727242
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.00000899
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:8Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:5
Pathogenic, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicMay 06, 2019PS3, PM2, PS4_moderate, PP4, PP5 -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityOct 13, 2023- -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenNov 01, 2020- -
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesJun 11, 2020The 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. -
Pathogenic, criteria provided, single submitterclinical testingGeneDxMay 26, 2021Published 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) -
Inherited Creutzfeldt-Jakob disease Pathogenic:1Other:1
not provided, no classification providedliterature onlyGeneReviews-Associated with genetic Creutzfeldt-Jakob disease phenotype. One of the five most common variants that account for 85% of genetic prion disease. -
Pathogenic, no assertion criteria providedliterature onlyOMIMOct 02, 2014- -
Fatal familial insomnia Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMOct 02, 2014- -
Huntington disease-like 1 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 01, 2024This 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.77
BayesDel_addAF
Pathogenic
0.33
D
BayesDel_noAF
Pathogenic
0.32
Cadd
Uncertain
25
Dann
Pathogenic
1.0
DEOGEN2
Benign
0.40
T;T;T;.
Eigen
Pathogenic
0.78
Eigen_PC
Pathogenic
0.74
FATHMM_MKL
Uncertain
0.85
D
M_CAP
Uncertain
0.22
D
MetaRNN
Pathogenic
0.96
D;D;D;D
MetaSVM
Pathogenic
0.82
D
MutationAssessor
Uncertain
2.5
M;M;.;.
MutationTaster
Benign
1.0
A;A
PrimateAI
Uncertain
0.66
T
PROVEAN
Benign
-1.5
N;N;N;N
REVEL
Pathogenic
0.76
Sift
Uncertain
0.0030
D;D;D;D
Sift4G
Uncertain
0.0030
D;D;D;D
Polyphen
1.0
D;D;.;.
Vest4
0.87
MutPred
0.90
Gain of methylation at E200 (P = 0.0168);Gain of methylation at E200 (P = 0.0168);Gain of methylation at E200 (P = 0.0168);Gain of methylation at E200 (P = 0.0168);
MVP
1.0
MPC
1.5
ClinPred
0.92
D
GERP RS
5.4
Varity_R
0.77
gMVP
0.90

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs28933385; hg19: chr20-4680464; API