20-4699818-G-A

Position:

• chr20-4699818-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PP3_Strong PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 4.33

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a strand (size 6) in uniprot entity PRIO_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) 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	Protein	UniProt
PRNP	NM_000311.5	c.598G>A	p.Glu200Lys	missense_variant	2/2	ENST00000379440.9	NP_000302.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRNP	ENST00000379440.9	c.598G>A	p.Glu200Lys	missense_variant	2/2	1	NM_000311.5	ENSP00000368752	P1
PRNP	ENST00000424424.2	c.598G>A	p.Glu200Lys	missense_variant	2/2	1		ENSP00000411599	P1
PRNP	ENST00000430350.2	c.598G>A	p.Glu200Lys	missense_variant	2/2	1		ENSP00000399376	P1
PRNP	ENST00000457586.2	c.598G>A	p.Glu200Lys	missense_variant	2/2	1		ENSP00000415284	P1

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

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

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:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 18, 2024	The most common pathogenic variant reported in association with Creutzfeldt-Jakob disease (CJD) (PMID: 1684755, 8614527, 23555862, 8618678, 22584955); Published functional studies demonstrate the variant results in PrP aggregates in brain extracts from transgeneic mice carrying this variant (PMID: 22072968); Mice that were inoculated with brain extract from affected individuals carrying this variant developed prion disease (PMID: 8614527); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 2572450, 20593190, 10360778, 20514992, 10079068, 25149502, 23723004, 25064618, 21094273, 22584955, 25522698, 17494694, 14761942, 23132868, 9813003, 21689662, 22318125, 23966072, 8618678, 20730466, 21552571, 21298055, 23555862, 19543376, 22912570, 20139714, 15366237, 23296137, 14967768, 11756597, 26791950, 27803826, 11839833, 8780103, 19822779, 18176009, 10090891, 19597763, 12197632, 17285519, 30369525, 30369528, 30755683, 30817871, 8614527, 31589614, 31965421, 25279981, 9864731, 32367297, 15459517, 1404799, 36939723, 36975162, 33159724, 37161596, 1684755, 22072968) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 06, 2019	PS3, PM2, PS4_moderate, PP4, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 13, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 11, 2020	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. -

Inherited Creutzfeldt-Jakob disease Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 02, 2014	- -
not provided, no classification provided	literature only	GeneReviews	-	Associated with genetic Creutzfeldt-Jakob disease phenotype. One of the five most common variants that account for 85% of genetic prion disease. -

Fatal familial insomnia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 02, 2014

- -

Huntington disease-like 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 01, 2024

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. -

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
LIST_S2	Uncertain	0.96	.;D;D;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

Other links and lift over

dbSNP: rs28933385; hg19: chr20-4680464;