Variant classification summary

NM_000041.4:c.526C>T

APOE · NP_000032.1:p.(Arg176Cys) · NM_000041.4

GRCh37: chr19:45412079 C>T · GRCh38: chr19:44908822 C>T

Gene: APOE Transcript: NM_000041.4

Final call

Benign

BA1 stand-alone benign

Variant details

Gene

APOE

Transcript

NM_000041.4

Protein

NP_000032.1:p.(Arg176Cys)

gnomAD AF

0.07424017237686671 (v4.1)

ClinVar

drug response

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Benign: BA1 is met because gnomAD grpmax filtering allele frequencies exceed the 5% stand-alone threshold.

Final determination: Under the generic ACMG/AMP 2015 fallback, BA1 alone supports a Benign classification.

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	Not met	Not met: APOE p.Arg176Cys is common (gnomAD v4.1 AF 7.424%) and ClinVar has no qualifying established pathogenic classification.	clinvar gnomad_v4 PMID:16103896 PMID:19667110
PS2	Not assessed	Not assessed: no documented proband disease phenotype, confirmed maternity and paternity, and absence of family history are available for this variant.
PS3	Not assessed	Not assessed: exact-variant studies reported LDL-C associations, but no validated functional assay for APOE p.Arg176Cys was identified.	PMID:16103896 PMID:19667110 PMID:8664327
PS4	Not met	Not met: reviewed studies report pharmacogenetic lipid-response associations, not affected-versus-control carrier counts enabling PS4 OR >5.0 with a confidence interval excluding 1.0.	PMID:16103896 PMID:17289397 PMID:19667110 gnomad_v4
PM1	Not met	Not met: no qualifying hotspot or critical domain is established, and Arg176Cys has gnomAD v4.1 AF 0.0742402 with 4609 homozygotes.	gnomad_v4 hotspots
PM2	Not met	Not met: allele frequency is 6.54% in gnomAD v2.1 and 7.42% in v4.1, far above the <=0.01% PM2 threshold.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no affected-proband observation or parental/offspring testing establishes this variant in trans with a pathogenic APOE allele.
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: zero qualifying same-residue comparator candidates were supplied for APOE Arg176, so a different pathogenic missense change cannot be confirmed.	pm5_candidates PMID:16103896 PMID:19667110
PM6	Not assessed	Not assessed: no documented assumed de novo occurrence or parental and family information is available for this variant.
PP1	Not assessed	Not assessed: zero documented affected relatives with familial genotypes or informative meioses demonstrate co-segregation for this variant.
PP2	Not met	Not met: the APOE missense variant occurs at gnomAD v4.1 AF 0.0742402 with 4609 homozygotes, inconsistent with low benign missense variation.	gnomad_v4 clinvar PMID:16103896 PMID:19667110
PP3	Not met	Not met: missense REVEL 0.588 is below the PP3 supporting threshold of 0.644.	revel
PP4	Not assessed	Not assessed: no case phenotype or family-history description is provided to establish a highly specific single-etiology disease presentation.
PP5	Not met	Not met: ClinVar's exact-variant expert-panel classification is drug response, not Pathogenic or Likely pathogenic, so PP5's required source assertion is absent.	clinvar
BA1	Met	Met: gnomAD grpmax FAF is 10.14% in v2.1 and 10.36% in v4.1, exceeding the 5% generic BA1 threshold with adequate observed-allele counts.	gnomad_v2 gnomad_v4 clinvar
BS1	Not assessed	Not assessed: grpmax FAF is 10.14–10.36%, but disorder prevalence, penetrance, allelic heterogeneity, and a maximum-credible-frequency calculation are unavailable.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD contains 465 v2.1 and 4,609 v4.1 homozygotes, but healthy-adult status and full early-age penetrance are not established.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no variant-specific assay showed normal APOE p.Arg176Cys protein function or splicing; available functional testing involved Arg224Gln.	PMID:16103896 PMID:19667110 PMID:8664327
BS4	Not assessed	Not assessed: no informative affected-member genotypes are documented to establish lack of segregation for this variant.
BP1	Not assessed	Not assessed: no curated APOE disease spectrum establishes that truncating variants primarily cause disease, the required BP1 gene-level premise.	PMID:16103896 PMID:19667110
BP2	Not assessed	Not assessed: no phase-resolved evidence shows APOE c.526C>T in trans or cis with a pathogenic variant under the BP2 conditions.
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 0.588 exceeds the BP4 supporting threshold of 0.29 and is therefore gray-zone.	revel
BP5	Not assessed	Not assessed: no disease case with a documented alternate molecular basis is provided for evaluating BP5.
BP6	Not met	Not met: the exact-variant ClinVar expert-panel result is drug response, while Benign/Likely benign labels are non-expert laboratory submissions.	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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