Variant classification summary

NM_000041.4:c.388T>C

APOE · NP_000032.1:p.(Cys130Arg) · NM_000041.4

GRCh37: chr19:45411941 T>C · GRCh38: chr19:44908684 T>C

Gene: APOE Transcript: NM_000041.4

Final call

Benign

BA1 stand-alone benign BP4 supporting

Variant details

Gene

APOE

Transcript

NM_000041.4

Protein

NP_000032.1:p.(Cys130Arg)

gnomAD AF

0.14852043380538965 (v4.1)

ClinVar

Uncertain significance

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Benign: BA1 is met because gnomAD AF 0.148520 exceeds the stand-alone threshold of 0.05.

2

Benign: BP4 is met at supporting strength because REVEL 0.229 is at or below the threshold of 0.29.

Final determination: Generic ACMG/AMP 2015 rules classify the variant as Benign because one stand-alone benign criterion, BA1, is met; BP4 provides additional supporting benign evidence.

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 assessed	Not assessed: no alternate-nucleotide p.Cys130Arg variant with an established pathogenic classification was documented, and ClinVar is conflicting without expert-panel review.	clinvar
PS2	Not assessed	Not assessed: no documented proband disease, family-history status, or confirmed maternity and paternity establishes a de novo occurrence.
PS3	Not assessed	Not assessed: no validated assay directly tested APOE p.Cys130Arg, and the available APOE4 mouse study did not mention this variant.	PMID:23060451
PS4	Not met	Not met: no reviewed source provides exact-variant case-control counts or an odds ratio with a 95% confidence interval meeting >5.0 and excluding 1.0.	PMID:11940689 PMID:15668424 PMID:20298421 PMID:21900891 PMID:26186657 PMID:23060451
PM1	Not met	Not met: no APOE C130 hotspot was found, and gnomAD v4.1 shows AF 0.148520 with 17,710 homozygotes, inconsistent with no benign variation.	gnomad_v4
PM2	Not met	Not met: gnomAD AF is 0.148520, far above the PM2 supporting threshold of <=0.0001.	gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: PM3 requires a recessive disorder and proven trans phase with a pathogenic variant, neither of which is established for this APOE variant.
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 qualifying pathogenic alternate missense at residue Cys130 was documented; the PM5 candidate set contained zero same-residue candidates.	pm5_candidates clinvar
PM6	Not assessed	Not assessed: no assumed de novo occurrence or parental testing documents that the variant is absent from both parents.
PP1	Not assessed	Not assessed: no affected relatives or informative meioses are documented to demonstrate cosegregation with disease.
PP2	Not met	Not met: p.Cys130Arg has gnomAD v4.1 AF 0.148520 with 17,710 homozygotes, inconsistent with a gene having low benign missense variation.	gnomad_v4 PMID:20298421
PP3	Not met	Not met: REVEL 0.229 is below the generic PP3 supporting threshold of 0.644 for this missense variant.	revel
PP4	Not assessed	Not assessed: no patient phenotype or family history is available to determine whether it is highly specific for a single-gene disease.
PP5	Not met	Not met: ClinVar has no exact-variant expert-panel pathogenic assertion, only conflicting ordinary laboratory submissions and no qualifying literature report.	clinvar
BA1	Met	Met: gnomAD total allele frequency is 0.148520, exceeding the BA1 stand-alone threshold of 0.05.	gnomad_v2 gnomad_v4
BS1	Not assessed	Not assessed: AF 0.148520 is high, but late-onset incomplete penetrance requires disorder-specific maximum-credible-frequency inputs not supplied here.	gnomad_v2 gnomad_v4 PMID:20298421
BS2	Not assessed	Not assessed: gnomAD reports 17,710 homozygotes, but provides no verified healthy-adult status or early-age full-penetrance assessment.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no validated assay directly demonstrated normal protein function or splicing for APOE p.Cys130Arg.	PMID:23060451
BS4	Not assessed	Not assessed: no tested affected relatives or documented non-segregation provides evidence against cosegregation.
BP1	Not met	Not met: APOE literature describes the common missense epsilon4 allele as a disease risk factor, not a primarily truncating disease mechanism.	PMID:20298421
BP2	Not assessed	Not assessed: the c.[305C>G;388T>C] ClinVar record lacks pathogenicity and patient-level phase evidence for the second allele.	clinvar
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	Met	Met at supporting strength: REVEL 0.229 is within the generic BP4 supporting threshold of <= 0.29 for this missense variant.	revel
BP5	Not assessed	Not assessed: no case links this variant to disease in a patient with a documented alternate molecular basis.
BP6	Not met	Not met: ClinVar has no exact-variant expert-panel benign assertion, and its benign entries are conflicting ordinary laboratory submissions.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.