LRP1B

Chr 2

LDL receptor related protein 1B

Also known as: LRP-1B, LRP-DIT, LRPDIT

NCBI Gene: 53353 ENSG00000168702 OMIM: 608766

The LRP1B protein is a low-density lipoprotein receptor family member that binds and internalizes ligands through receptor-mediated endocytosis at the cell surface. Mutations cause neurodevelopmental disorders with intellectual disability and autism spectrum disorder features, inherited in an autosomal dominant pattern. This gene is highly constrained against loss-of-function variants in the population, indicating intolerance to such mutations.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the low density lipoprotein (LDL) receptor family. These receptors play a wide variety of roles in normal cell function and development due to their interactions with multiple ligands. Disruption of this gene has been reported in several types of cancer. [provided by RefSeq, Jun 2016]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.32

Clinical Summary— LRP1B

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.26) despite low pLI — interpret in context.

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ClinVar Variants

6 unique Pathogenic / Likely Pathogenic· 462 VUS of 696 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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?

0.32LOEUF

pLI 0.000

Z-score 10.77

OE 0.26 (0.21–0.32)

Highly constrained

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

Missense Constraint?

1.93Z-score

OE missense 0.89 (0.86–0.92)

2148 obs / 2414.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.26 (0.21–0.32)

0≤0.351.4

Missense OE?0.89 (0.86–0.92)

0≤0.61.4

Synonymous OE?1.11

0≤1.21.6

LoF obs/exp: 63 / 244.9Missense obs/exp: 2148 / 2414.6Syn Z: -2.56

This gene — mechanism propensity

0.6550th %ile

GOF

0.7029th %ile

LOF

0.3941th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction 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.

ClinVar Variant Classifications

696 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic6

VUS462

Likely Benign84

Benign72

Conflicting4

Likely Pathogenic

462

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	5	0	1	6
VUS	3	459	0	0	462
Likely Benign	0	34	9	41	84
Benign	0	20	17	35	72
Conflicting	—				4
Total	3	518	26	77	628

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

View in ClinVar →

20 pathogenic / likely-pathogenic (of 44) ClinVar copy-number / structural variants overlap LRP1B — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →