Variant classification summary

NM_000384.3:c.10580G>A

APOB · NP_000375.3:p.(Arg3527Gln) · NM_000384.3

GRCh37: chr2:21229160 C>T · GRCh38: chr2:21006288 C>T

Gene: APOB Transcript: NM_000384.3

Final call

VUS

PS3 supporting PS4 strong PP3 supporting BA1 stand-alone benign

Variant details

Gene

APOB

Transcript

NM_000384.3

Protein

NP_000375.3:p.(Arg3527Gln)

gnomAD AF

0.0004207304227132465 (v4.1)

ClinVar

Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 supporting: exact-variant LDL-receptor binding was defective and cosegregated with hypercholesterolemia.

2

PS4 strong: exact-variant odds ratios were 7.0 and 78, with confidence intervals excluding 1.

3

PP3 supporting: REVEL 0.735 exceeded the missense threshold.

4

BA1 stand-alone benign: Amish allele frequency was 6.79825%, above 5%.

Final determination: Under generic ACMG/AMP 2015 fallback rules, 1 strong plus 2 supporting pathogenic criteria satisfies Likely Pathogenic and BA1 independently satisfies Benign; satisfying both sides makes the final classification VUS.

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: the reviewed pathogenic comparator is APOB Arg3500Gln, whereas this variant is Arg3527Gln, with no established alternate nucleotide change yielding Arg3527Gln.	PMID:2563166
PS2	Not assessed	Not assessed: no documented de novo observation with confirmed maternity and paternity, disease phenotype, and absent family history is available for this variant.
PS3	Met	Met at supporting: patient-derived LDL with exact Arg3500Gln showed defective LDL-receptor binding and cosegregated with hypercholesterolemia, but causality was described as circumstantial.	PMID:2563166
PS4	Met	Met: exact-variant case-control associations were OR 7.0 (95% CI 2.2–22) and OR 78 (95% CI 16–388), both above 5.0 with intervals excluding 1.
PM1	Not assessed	Not assessed: no authoritative APOB domain table or qualifying R3527 hotspot is available; the cited hotspot is at residue 3500, not 3527.	PMID:2563166 cspec
PM2	Not met	Not met: gnomAD v4.1 frequency is 0.0004207304, exceeding the generic PM2 supporting threshold of 0.0001.	gnomad_v2 gnomad_v4 PMID:25741868
PM3	N/A	Not applicable: the evaluated APOB hypercholesterolemia disorder is semidominant/autosomal dominant, whereas PM3 is restricted to recessive disorders.	cspec
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: reviewed APOB missense comparators occur at residues 3492 and 3500, and no pathogenic alternate missense change at residue 3527 was established.	PMID:11781700 PMID:2563166 pm5_candidates
PM6	Not assessed	Not assessed: no assumed de novo occurrence without confirmed parental testing is documented for this variant.
PP1	Not assessed	Not assessed: no affected-relative genotypes, informative meioses, or variant-specific segregation data are documented for this variant.
PP2	Not assessed	Not assessed: no gene-level benign-missense rate and missense-mechanism assessment establishing both PP2 requirements is available.
PP3	Met	Met at supporting strength: REVEL 0.735 meets the supplied PP3 threshold of >= 0.644 for this missense variant.	revel
PP4	Not assessed	Not assessed: no patient-specific phenotype or family-history description is available to evaluate the PP4 specificity requirement.
PP5	Not met	Not met: ClinVar has no exact-variant expert-panel submission (expert-panel count 0), so ordinary pathogenic laboratory submissions cannot trigger PP5.	clinvar
BA1	Met	Met: Amish allele frequency is 6.79825% (62/912), exceeding the generic BA1 stand-alone threshold of 5%.	gnomad_v4 PMID:25741868
BS1	Not met	Not met: Overall gnomAD v4.1 frequency is 0.0004207304, below the generic BS1 default of 0.01 despite an ancestry-specific Amish founder frequency.	gnomad_v2 gnomad_v4 cspec PMID:25741868
BS2	Not assessed	Not assessed: gnomAD reports one homozygote, but healthy-adult status and full early-age penetrance are not documented.	gnomad_v2 gnomad_v4 PMID:25741868
BS3	Not assessed	Not assessed: available testing showed defective LDL-receptor binding for the exact variant, with no study demonstrating preserved APOB function or normal splicing.	PMID:2563166
BS4	Not assessed	Not assessed: no affected relative lacking this variant or other variant-specific evidence of non-segregation is documented.
BP1	Not assessed	Not assessed: no APOB-specific variant-spectrum evidence shows that disease is caused primarily by truncating rather than missense variants.
BP2	Not assessed	Not assessed: no second pathogenic variant or parental/offspring phase data establish whether APOB p.Arg3527Gln is in trans or cis.	PMID:2563166
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: REVEL 0.735 exceeds the supplied BP4 supporting threshold of <= 0.29 for this missense variant.	revel
BP5	Not assessed	Not assessed: no alternate molecular basis for disease is documented for the patient, which is required to evaluate BP5.
BP6	Not met	Not met: ClinVar has no exact-variant expert-panel benign or likely-benign classification (expert-panel count 0), so BP6 is not triggered.	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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