Variant classification summary

NM_000311.5:c.598G>A

PRNP · NP_000302.1:p.(Glu200Lys) · NM_000311.5

GRCh37: chr20:4680464 G>A · GRCh38: chr20:4699818 G>A

Gene: PRNP Transcript: NM_000311.5

Final call

Likely Pathogenic

PS1 strong PM2 supporting PP1 supporting PP3 supporting

Variant details

Gene

PRNP

Transcript

NM_000311.5

Protein

NP_000302.1:p.(Glu200Lys)

gnomAD AF

8.055111835933482e-06 (v4.1)

ClinVar

Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Likely Pathogenic: PS1 strong is supported by the previously reported PRNP E200K change.

2

Likely Pathogenic: PM2 supporting is supported by the very low gnomAD v4.1 frequency and zero homozygotes.

3

Likely Pathogenic: PP1 supporting is supported by familial CJD segregation and lod score greater than 4.8.

4

Likely Pathogenic: PP3 supporting is supported by REVEL 0.761.

Final determination: Under the generic ACMG/AMP 2015 fallback rules, one strong pathogenic criterion plus at least two supporting pathogenic criteria yields Likely Pathogenic.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	Not applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Met	Met: the exact PRNP p.Glu200Lys (E200K) change was previously reported in familial prion disease, with SpliceAI maximum delta 0.001.	PMID:9813003 clinvar spliceai
PS2	Not assessed	Not assessed: no documented proband-level de novo finding with confirmed maternity and paternity and no family history.
PS3	Not met	Not met: E200K showed only a small 1.7 ± 0.2 kJ/mol stability reduction in one recombinant biophysical study without validated, reproducible disease-relevant functional evidence.	PMID:9813003
PS4	Not assessed	Not assessed: reported affected carriers lack matched control counts, odds ratio, and confidence interval required to test OR >5.0 with CI excluding 1.0.	PMID:1469441 gnomad_v4
PM1	Not assessed	Not assessed: no approved PRNP domain table or established residue-200 hotspot with demonstrated absence of benign variation is available.
PM2	Met	Met at Supporting: gnomAD v4.1 AF is 8.05511e-06, below the supplied PM2 Supporting threshold of 0.0001, with zero homozygotes.	gnomad_v4 gnomad_v2
PM3	N/A	Not applicable: PRNP-associated prion disease is described as autosomal dominant, whereas PM3 requires a recessive disorder and a pathogenic variant in trans.
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no documented pathogenic alternative missense substitution at PRNP residue 200 is available for comparison.
PM6	Not assessed	Not assessed: no proband-level evidence establishes this variant as assumed de novo without parental confirmation.
PP1	Met	Met at supporting strength: Lys200 segregated with familial CJD and showed lod score >4.8, but affected meioses and penetrance details are incomplete.	PMID:8105682
PP2	Not assessed	Not assessed: no gene-wide benign-missense rate and no documented PRNP missense-mechanism assessment are supplied.
PP3	Met	Met at supporting: missense REVEL 0.761 meets the >=0.644 PP3 supporting threshold but does not reach the >=0.773 moderate threshold.	revel
PP4	Not assessed	Not assessed: the patient's phenotype and family history are not available to determine whether they are highly specific for a single genetic disease.
PP5	Not met	Not met: ClinVar has zero expert-panel submissions, so ordinary laboratory, aggregate, and primary-literature pathogenic reports cannot trigger PP5.	clinvar PMID:10360778 PMID:11839833
BA1	Not met	Not met: gnomAD v4.1 grpmax FAF is 5.53e-06, far below the BA1 stand-alone threshold of 0.05.	gnomad_v4 clinvar
BS1	Not met	Not met: gnomAD v4.1 grpmax FAF is 5.53e-06, far below the generic BS1 default threshold of 0.01.	gnomad_v4 PMID:8105682
BS2	N/A	Not applicable: healthy carriers over age 65 and reported incomplete penetrance conflict with the required full early-age penetrance condition.	PMID:8105682
BS3	Not met	Not met: E200K retained similar structure but showed a measurable 1.7 ± 0.2 kJ/mol stability reduction, so the study does not show no damaging effect.	PMID:9813003
BS4	Not assessed	Not assessed: no affected relative is documented to lack the variant, and no non-segregation dataset is provided.
BP1	Not assessed	Not assessed: the evidence does not establish that PRNP disease is caused primarily by truncating rather than missense variants.
BP2	Not assessed	Not assessed: a report describes two pathogenic PRNP variants and phase testing, but the available abstract does not state whether E200K is in trans or cis.
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: missense REVEL 0.761 exceeds the <=0.29 BP4 supporting threshold, so the score does not support no impact.	revel
BP5	Not assessed	Not assessed: no case carrying this variant is documented with an alternate molecular basis for disease.
BP6	Not met	Not met: no exact-variant ClinVar expert-panel Benign or Likely benign classification is present, and the record is Pathogenic.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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