LRP8

Chr 1

LDL receptor related protein 8

Also known as: APOER2, HSZ75190, LRP-8, MCI1

NCBI Gene: 7804 ENSG00000157193 UniProt: Q14114 OMIM: 602600

The LRP8 protein functions as a cell surface receptor for Reelin and apolipoprotein E, playing a critical role in neuronal migration and layering during embryonic brain development through the Reelin signaling pathway. Mutations in LRP8 are associated with susceptibility to myocardial infarction with autosomal dominant inheritance. This gene is highly constrained against loss-of-function mutations, suggesting that complete loss of LRP8 function may be incompatible with normal development.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the low density lipoprotein receptor (LDLR) family. Low density lipoprotein receptors are cell surface proteins that play roles in both signal transduction and receptor-mediated endocytosis of specific ligands for lysosomal degradation. The encoded protein plays a critical role in the migration of neurons during development by mediating Reelin signaling, and also functions as a receptor for the cholesterol transport protein apolipoprotein E. Expression of this gene may be a marker for major depressive disorder. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jun 2011]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.221 OMIM phenotype

Clinical Summary— LRP8

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

113 VUS of 160 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.22LOEUF

pLI 1.000

Z-score 5.67

OE 0.11 (0.06–0.22)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.52Z-score

OE missense 0.70 (0.64–0.76)

382 obs / 548.0 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.11 (0.06–0.22)

0≤0.351.4

Missense OE?0.70 (0.64–0.76)

0≤0.61.4

Synonymous OE?0.88

0≤1.21.6

LoF obs/exp: 5 / 46.9Missense obs/exp: 382 / 548.0Syn Z: 1.45

This gene — mechanism propensity

0.4389th %ile

GOF

0.7028th %ile

LOF

0.62top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFLOEUF 0.22

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

160 submitted variants in ClinVar

ClinVar

Classification Summary

VUS113

Likely Benign18

Benign8

Conflicting1

113

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	0	113	0	0	113
Likely Benign	0	9	4	5	18
Benign	0	0	1	7	8
Conflicting	—				1
Total	0	122	5	12	140

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

10 pathogenic / likely-pathogenic (of 14) ClinVar copy-number / structural variants overlap LRP8 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →