The PRNP NM_000311.5:c.598G>A (NP_000302.1:p.(Glu200Lys)) missense variant has previously been reported in somatic cancers (COSMIC; COSV109710272, n = 1 time). Based on available guidelines, this variant is considered to be Likely Pathogenic.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic classification under the recorded framework.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.PRNP encodes a glycosylphosphatidylinositol-anchored cell-surface glycoprotein that can form aggregates and contains a region of repeated amino-acid sequences. Changes in PRNP are associated with several prion diseases and related neurodegenerative disorders, including Creutzfeldt-Jakob disease, fatal familial insomnia, Gerstmann-Straussler disease, and kuru. PRNP has no established primary role in cancer.
The recorded framework is Generic ACMG/AMP 2015 with ClinGen SVI recommendations. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
Met: the exact PRNP p.Glu200Lys (E200K) change was previously reported in familial prion disease, with SpliceAI maximum delta 0.001.
Met at Supporting: gnomAD v4.1 AF is 8.05511e-06, below the supplied PM2 Supporting threshold of 0.0001, with zero homozygotes.
Met at supporting strength: Lys200 segregated with familial CJD and showed lod score >4.8, but affected meioses and penetrance details are incomplete.
Met at supporting: missense REVEL 0.761 meets the >=0.644 PP3 supporting threshold but does not reach the >=0.773 moderate threshold.
No benign criterion marked as applied in the recorded assessment.
Likely Pathogenic: PS1 strong plus PM2, PP1, and PP3 supporting satisfy the generic ACMG/AMP fallback combination rule.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 13 / 1,613,882 alleles. Recorded AF 8.05511e-06. Recorded homozygote count 0.
This variant is present in gnomAD v2.1 (AF= 3.97668e-06; MAF= 0.00040%, 1/251466 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.89084e-05; MAF= 0.00289%, 1/34592 alleles, homozygotes = 0).
Not available in gnomAD-Canada v1.0.
Recorded REVEL score: 0.761. Refer to the recorded PP3/BP4 rationale for interpretation.
10 Pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
No standalone functional evidence summary is recorded in evidence_summary.functional.
This variant has previously been reported in somatic cancers (COSMIC; COSV109710272, n = 1 times).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under Generic ACMG/AMP 2015 with ClinGen SVI recommendations, with the data and sources behind each one.
28 criteria with recorded statuses: 4 met · 7 not met · 11 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
The available evidence supports PP1 at supporting strength from a familial PRNP Lys200 segregation report, while PS2 and PM6 lack proband-level parental testing and BS4 lacks documented affected non-segregation.
The published segregation report includes a lod score greater than 4.8 but does not provide sufficient complete meiosis and penetrance detail for a stronger PP1 assignment.
The only variant-specific functional study was a single recombinant biophysical assay with a wild-type comparator; its modest stability reduction is insufficiently validated and disease-proximal to assign PS3, and it precludes BS3.
No independent, validated clinical-laboratory functional assay or reproducible disease-relevant functional endpoint was identified for PRNP E200K.
Generic ACMG/AMP rules govern because no PRNP VCEP is present.
PS4 is not assessed because the reviewed reports do not provide the required case-control OR/CI or sufficient counts to calculate them.
PP4 and BP5 are not assessed because current-patient phenotype/family-history specificity and an alternate molecular diagnosis are not documented.
PP5 and BP6 are not met because the exact ClinVar record has zero expert-panel submissions and does not provide the required qualifying classification source.
The consequence is missense, so PP3 and BP4 are adjudicated exclusively through REVEL; SpliceAI is not double-counted or substituted across predictor paths.
REVEL 0.761 supports PP3 at supporting strength but does not meet any BP4 threshold.
No criteria match.
PS1 is met because the assessed variant is PRNP p.Glu200Lys (E200K), an already reported PRNP E200K mutation associated with familial prion disease. The directly reviewed functional paper explicitly studied the same E200K protein variant, and the case evidence identifies the exact p.Glu200Lys ClinVar record as pathogenic with multiple concordant submitters. SpliceAI maximum delta is 0.001, so the available splice prediction does not suggest that the prior disease association is primarily explained by an alternative splicing consequence.
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. ... Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
PM2 is met at Supporting strength under the supplied generic SVI threshold. In default all-comers gnomAD v4.1, the variant has AF=8.05511e-06 (13/1,613,882 alleles), 0 homozygotes, and filtering grpmax FAF=5.53e-06. The AF is <=0.0001, the supplied PM2 Supporting cutoff. gnomAD v2.1 independently shows 1/251,466 alleles and 0 homozygotes; the non-cancer v2.1 exome subset also shows 1/236,938 alleles and 0 homozygotes, but no VCEP rule requires that subset, so the default all-comers data govern.
Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
PMID:8105682 reports that the PRNP Lys200 substitution segregated with familial Creutzfeldt-Jakob disease in Libyan Jewish pedigrees and was genetically linked to disease with a lod score greater than 4.8. This supports co-segregation of the p.Glu200Lys variant with disease in affected family members, but the available extract does not provide a complete pedigree-level count of affected meioses or enough detail to justify stronger PP1 strength. Healthy elderly Lys200 carriers were also reported, so penetrance and age-related interpretation require human review.
PP1: Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. ... Note: May be used as stronger evidence with increasing segregation data.
The variant is a missense substitution, NP_000302.1:p.(E200K), so the governing generic rule requires the missense REVEL path only. REVEL is 0.761, meeting the published ClinGen SVI supporting PP3 threshold of >= 0.644 (Pejaver et al. 2022, PMID:36413997), but not the moderate threshold of >= 0.773. SpliceAI is not used for PP3 in this missense situation, and BayesDel is not available because no generic ACMG-strength calibration is established.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
PMID:9813003 directly evaluated recombinant human PRNP E200K (p.Glu200Lys) against wild-type protein using circular dichroism, guanidine-hydrochloride equilibrium unfolding, and thermal denaturation. The study reported essentially indistinguishable secondary and tertiary structures and only a small neutral-pH stability reduction (ΔΔG[D]50% 1.7 ± 0.2 kJ/mol; Tm 67.0 ± 0.9 °C versus 70.2 ± 0.1 °C for wild type), with no significant difference in the acidic-pH folding intermediate. This is biologically relevant and includes a wild-type comparator, but the available evidence is a single recombinant biophysical study, does not demonstrate a disease-relevant functional endpoint, and does not establish validation, reproducibility, or robustness in a clinical diagnostic laboratory setting. Therefore it does not satisfy the generic PS3 requirement for well-established functional evidence, and no PS3 strength is assigned.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
The exact ClinVar record for NM_000311.5:c.598G>A is Pathogenic, but the audit reports zero expert-panel submissions; the record consists of ordinary laboratory and literature-only assertions. Under the instructed generic gate, those sources cannot trigger PP5. The reviewed papers report E200K in familial CJD, including 39 E200K carriers in PMID:20593190 and an E200K CJD case in PMID:11839833, but they are primary evidence available for independent evaluation rather than an exact-variant ClinVar expert-panel classification. PP5 is not met.
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
BA1 is not met. The default all-comers gnomAD v4.1 record shows AF=8.05511e-06 (13/1,613,882 alleles; 0 homozygotes), and the filtering grpmax FAF is 5.53e-06. This is far below the generic BA1 stand-alone threshold of >=0.05; the highest observed ancestry point estimate, Admixed American AF=3.33322e-05 from 2/60,002 alleles, is not used for BA1 because FAF rather than popmax AF is required. No VCEP-specific population source applies, and the observed population frequency does not provide a stand-alone benign basis despite the pathogenic ClinVar consensus.
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
BS1 is not met. The gnomAD v4.1 filtering grpmax FAF is 5.53e-06, well below the generic default BS1 threshold of >=0.01, with no ancestry group showing a qualifying filtering frequency from at least 2,000 observed alleles. The variant is a known PRNP E200K disease-associated allele, and the available literature reports healthy elderly carriers suggesting incomplete penetrance; therefore a default 1% cutoff should not be treated as an unconditional disease-frequency limit. Nevertheless, the observed FAF is orders of magnitude below 1%, so BS1 is not supported even without a maximum-credible-frequency calculation.
Allele frequency is greater than expected for the disorder.
PMID:9813003 does not show absence of a damaging effect for PRNP E200K. Although the recombinant protein had secondary and tertiary structures essentially indistinguishable from wild type, the study measured a small but reported reduction in neutral-pH stability (ΔΔG[D]50% 1.7 ± 0.2 kJ/mol; Tm 67.0 ± 0.9 °C versus 70.2 ± 0.1 °C for wild type). The result therefore cannot support BS3, which requires well-established functional studies showing no damaging effect on protein function or splicing.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
The variant is a missense substitution, NP_000302.1:p.(E200K), so the governing generic rule requires the missense REVEL path only. REVEL is 0.761, which exceeds the generic BP4 supporting cutoff of <= 0.29 and therefore does not support no impact. SpliceAI max delta 0.001 is not counted for BP4 because splice predictions cannot substitute for an indeterminate/non-supportive REVEL result in a missense variant, and BayesDel has no generic ACMG-strength calibration.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
The exact ClinVar record is Pathogenic and the audit reports zero expert-panel submissions; no exact-variant expert-panel Benign or Likely benign classification is present. Ordinary laboratory submissions, aggregate ClinVar labels, and non-expert assertions cannot trigger BP6 under the instructed generic rule. BP6 is not met.
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
The available evidence does not document a proband with confirmed de novo NM_000311.5:c.598G>A (p.Glu200Lys), confirmed maternity and paternity, or absence of a family history. Parental genotypes and family-history information are not provided, so the PS2 requirements cannot be assessed.
PS2: De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
The governing ACMG/AMP rule requires a case-control prevalence comparison with relative risk or odds ratio >5.0 and a confidence interval that does not include 1.0. The reviewed literature reports affected E200K carriers or familial clustering, including two related CJD patients in PMID:2572450 and six Chilean CJD families in PMID:1469441, but it does not provide unaffected-control counts, a matched-ancestry control frequency paired with case counts, an odds ratio, or a confidence interval. These observations therefore cannot establish the required case-control statistic. gnomAD v4.1 reports 13/1,613,882 alleles overall, but no affected-case numerator is available for a case-control calculation. No PS4 conclusion is made.
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0.
PM1 cannot be assessed from the supplied evidence. No VCEP covers PRNP, vcep_materials.json contains no PRNP domain table, and the available evidence does not establish residue 200 as a mutational hotspot or as part of a critical and well-established functional domain lacking benign variation. The exact variant is reported once in COSMIC, but the governing generic rule does not provide a somatic-hotspot route and the evidence does not establish a residue-level hotspot.
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
PM5 cannot be assessed because the supplied evidence does not document a different missense substitution at PRNP residue 200 that has been independently determined to be pathogenic. The PM5 candidate file contains no comparator candidates, and the exact E200K record cannot serve as the required different missense change.
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. ... Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
The available evidence does not document an assumed de novo NM_000311.5:c.598G>A (p.Glu200Lys) event in a proband. No parental genotypes or other evidence establishing de novo status without maternity and paternity confirmation are provided.
PM6: Assumed de novo, but without confirmation of paternity and maternity.
PP2 cannot be assessed because the supplied evidence is variant-specific and does not provide a gene-wide estimate showing a low rate of benign missense variation in PRNP together with a documented conclusion that missense variants are a common disease mechanism. The rare population frequency of this individual variant and its pathogenic ClinVar record do not establish both PP2 requirements.
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
The governing rule requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology. The case materials identify PRNP p.Glu200Lys and literature-associated familial prion diseases, but they do not provide this patient's phenotype or family history in a form that permits assessment of highly specific disease features or exclusion of phenocopies. Published E200K CJD observations cannot substitute for the current patient's phenotype. PP4 is not assessed.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
No affected family member carrying a different genotype, or other documented affected relative in whom NM_000311.5:c.598G>A fails to segregate, is identified. The reported familial segregation evidence cannot be converted into evidence for lack of segregation, and no phenocopy assessment is available.
BS4: Lack of segregation in affected members of a family.
BP1 cannot be assessed because the supplied evidence does not establish that PRNP disease is caused primarily by truncating variants. The evidence documents a missense E200K disease-associated variant, but that single variant and its literature cannot determine the gene-wide relative contribution of truncating versus missense disease mechanisms.
Missense variant in a gene for which primarily truncating variants are known to cause disease.
BP2 requires documented allelic phase relative to a pathogenic variant. A PubMed abstract reports one patient with two pathogenic PRNP variants and states that phase testing was performed by restriction-enzyme digestion followed by sequence analysis, but the available text does not identify the partner variant or report whether PRNP p.(Glu200Lys) was in trans or in cis. The required phase observation therefore cannot be confirmed.
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
The governing rule requires the variant to be found in a case with an alternate molecular basis for disease. The available case and literature materials describe PRNP E200K-associated prion disease, population observations, or unrelated functional studies, but do not document an alternate molecular diagnosis in a case carrying this variant. BP5 cannot be assessed from the available evidence.
Variant found in a case with an alternate molecular basis for disease.
PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_000311.5:c.598G>A in PRNP is a missense substitution predicted to produce NP_000302.1:p.(Glu200Lys). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PVS1 for PRNP, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_null_variant_class
PM3 is not applicable because its governing definition is limited to recessive disorders. The available case evidence describes PRNP-associated prion disease as typically inherited in an autosomal dominant manner; therefore, the recessive trans configuration required by PM3 is not the applicable inheritance model for this case.
For recessive disorders, detected in trans with a pathogenic variant
PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_000311.5:c.598G>A in PRNP is a missense substitution predicted to produce NP_000302.1:p.(Glu200Lys). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PM4 for PRNP, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
BS2 is not applicable under its stated applicability condition. Gabizon et al. reported some healthy elderly PRNP Lys200 carriers over age 65 and suggested incomplete penetrance. PRNP E200K-associated familial CJD is late-onset and does not satisfy the rule's requirement that full penetrance be expected at an early age; therefore the observation of healthy older carriers cannot be used to apply BS2.
Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_000311.5:c.598G>A in PRNP is a missense substitution predicted to produce NP_000302.1:p.(Glu200Lys). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP3 for PRNP, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_repeat_region_indel
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_000311.5:c.598G>A in PRNP is a missense substitution predicted to produce NP_000302.1:p.(Glu200Lys). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for PRNP, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
Every interpreted variant in PRNP, mapped onto the exon structure of NM_000311.5. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| Admixed American2 / 60,002 | 3.3e-05 |
| European (Finnish)1 / 63,946 | 1.6e-05 |
| European (non-Finnish)10 / 1,180,000 | 8.5e-06 |
| Admixed American1 / 34,592 | 2.9e-05 |
This variant is present in gnomAD v4.1 (AF= 8.05511e-06; MAF= 0.00081%, 13/1613882 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 3.33322e-05; MAF= 0.00333%, 2/60002 alleles, homozygotes = 0); grpmax FAF= 5.53e-06.
This variant is present in gnomAD v2.1 (AF= 3.97668e-06; MAF= 0.00040%, 1/251466 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.89084e-05; MAF= 0.00289%, 1/34592 alleles, homozygotes = 0).
Not available in gnomAD-Canada v1.0.
The variant is a missense substitution, NP_000302.1:p.(E200K), so the governing generic rule requires the missense REVEL path only. REVEL is 0.761, meeting the published ClinGen SVI supporting PP3 threshold of >= 0.644 (Pejaver et al. 2022, PMID:36413997), but not the moderate threshold of >= 0.773. SpliceAI is not used for PP3 in this missense situation, and BayesDel is not available because no generic ACMG-strength calibration is established.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
The variant is a missense substitution, NP_000302.1:p.(E200K), so the governing generic rule requires the missense REVEL path only. REVEL is 0.761, which exceeds the generic BP4 supporting cutoff of <= 0.29 and therefore does not support no impact. SpliceAI max delta 0.001 is not counted for BP4 because splice predictions cannot substitute for an indeterminate/non-supportive REVEL result in a missense variant, and BayesDel has no generic ACMG-strength calibration.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_000311.5:c.598G>A in PRNP is a missense substitution predicted to produce NP_000302.1:p.(Glu200Lys). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for PRNP, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.761. BayesDel score = 0.324599.
8 paper records listed. 2 cited in the classification.
A Lys200 substitution segregates with CJD and is reported here to be genetically linked to CJD with a lod score of > 4.8.
Location Abstract
Context Familial Creutzfeldt-Jakob disease study in Libyan Jewish pedigrees using PRNP mutation analysis and genetic linkage assessment.
the E200K mutation resulted in a very small destabilization of the protein.
Location Abstract; Results, paragraphs describing circular dichroism and thermodynamic stability; Table I; Discussion, paragraphs discussing E200K
Context In vitro biophysical characterization of recombinant human PrP(90–231) containing E200K, expressed in Escherichia coli; circular dichroism spectroscopy, guanidine hydrochloride equilibrium unfolding, and thermal denaturation at neutral and acidic pH.
A novel phenotype of familial Creutzfeldt-Jakob disease (CJD) with mutated codon 200 of the prion protein gene (PRNP) coupled with the valine codon 129 (E200K-129V haplotype)
Abstract
To report a 53-year-old woman with intractable insomnia as her initial symptom of disease.
Abstract
We have found the codon 200Lys mutation in 6 Chilean CJD families, including a family in the rural case cluster in Chillán.
Abstract
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 8.05511e-06; MAF= 0.00081%, 13/1613882 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 3.33322e-05; MAF= 0.00333%, 2/60002 alleles, homozygotes = 0); grpmax FAF= 5.53e-06.
This variant is present in gnomAD v2.1 (AF= 3.97668e-06; MAF= 0.00040%, 1/251466 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.89084e-05; MAF= 0.00289%, 1/34592 alleles, homozygotes = 0).
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Pathogenic (10 clinical laboratories). (ClinVarID = 13398)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.761. BayesDel score = 0.324599.
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV109710272, n = 1 times).
This variant does not lie in a statistically significant hotspot.