GeneBe

LDLRAP1

protein-coding

low density lipoprotein receptor adaptor protein 1

Gene summary

The protein encoded by this gene is a cytosolic protein which contains a phosphotyrosine binding (PTD) domain. The PTD domain has been found to interact with the cytoplasmic tail of the LDL receptor. Mutations in this gene lead to LDL receptor malfunction and cause the disorder autosomal recessive hypercholesterolaemia. [provided by RefSeq, Jul 2008]

MANE transcript

NM_015627.3

Inheritance

AR

ClinVar variants

P:72U:186B:208

Top phenotype

Hypercholesterolemia, familial, 4

gnomAD constraint

pLI —, LoF o/e 0.69

Max pathogenic AF

—

Genomic locus

chr1:25,543,604-25,591,200

External References & Databases

Ensembl (ENSG00000157978)NCBI Gene (26119)OMIM (605747)HGNC:18640GenCCUniProt (Q5SW96)AlphaFoldClinVar (LDLRAP1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~47.6 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hypercholesterolemia, familial, 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011374

Submitter: Genomics England PanelApp

hypercholesterolemia, familial, 4DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011374

Submitter: Natera

hypercholesterolemia, familial, 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011374

Submitter: Labcorp Genetics (formerly Invitae)

homozygous familial hypercholesterolemiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018328

Submitter: Orphanet

hypercholesterolemia, familial, 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011374

Submitter: PanelApp Australia

hypercholesterolemia, familial, 4DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011374

Submitter: ClinGen

The relationship between *LDLRAP1* and familial hypercholesterolemia 4, inherited in the autosomal recessive pattern has been evaluated using the ClinGen Clinical Validity Framework as of July, 2020. This association was made using case-level and experimental data. Familial hypercholesterolemia 4 is characterized by severe hypercholesterolemia and large tendon xanthomas. Increased plasma LDL levels occur as a result of defect in interaction with ***LDLR*** (PMID: 25399932). The *LDLRAP1* gene encodes a cytosolic protein which contains a phosphotyrosine binding (PTB) domain, that is essential for interaction with the cytoplasmic tail of *LDLR*. More than 20 variants, mostly frameshift and nosense, have been reported in humans. *LDLRAP1* has been associated with familial hypercholesterolemia 4 as early as 2001 (Garcia et al, 2001; PMID: 11326085). Summary of Case Level Data (12 points): The association is seen in at least 8 probands in 2 publications (PMID: 12464675, 11326085). Variants in this gene segregated with disease in additional family members (PMID: 11326085). More case-level evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. The mechanism for disease is biallelic loss of function. Summary of Experimental Data (6 points): The LDLRAP1 protein has a role in the internalization of LDLR for plasma LDL clearance (PMID: 12451172). It physically interacts with *LDLR* and has a function in cholesterol metabolism similar to *LDLR* and *APOB*, mutations in which also cause familial hypercholesterolemia (PMID: 12221107, 16179341). Mouse models with *LDLRAP1* alterations recapitulate the human hypercholesterolemia phenotype (PMID: 12746448). Rescue of *LDLR* uptake and degradation by wild-type protein expression in patient cells has been demonstrated (PMID: 12464675). In summary, the *LDLRAP1*-Familial hypercholesterolemia 4 gene-disease relationship is definitive. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

Clinical Genomic Database (CGD)

Hypercholesterolemia, familial, 4AR

Manifestation: Cardiovascular; Dermatologic

Intervention: Cardiovascular

Rationale: Interventions to maintain lipid profiles at a more desirable level can decrease morbidity/mortality, such as relates to CAD

Refs: 11326085; 15599766; 21872251Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to LDLRAP1 variants in ClinVar

10 Conditions Cataloged
Hypercholesterolemia, familial, 4Total: 437
Cardiovascular phenotypeTotal: 245
Familial hypercholesterolemiaTotal: 106
not specifiedTotal: 93
not providedTotal: 50
LDLRAP1-related disorderTotal: 10
LDLRAP1-related disordersTotal: 3
Autosomal recessive inheritanceTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015627.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
2
clinvar
181
clinvar
2
clinvar
 185
missense
1
clinvar
182
clinvar
22
clinvar
3
clinvar
 208
nonsense
13
clinvar
5
clinvar
2
clinvar
 20
start loss
2
clinvar
 2
frameshift
22
clinvar
16
clinvar
 38
splice donor/acceptor (+/-2bp)
2
clinvar
11
clinvar
 13
Total37351862035466

Highest pathogenic variant AF is 0.000033549208

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 64 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_015627.3RefSeqNP_056442.29MANE Select
ENST00000374338.5EnsemblENSP00000363458.49MANE Select
ENST00000718277.1EnsemblENSP00000520715.19Standard
ENST00000718277.2EnsemblENSP00000520715.19Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Endocytosis - Homo sapiens (human)
  • Cholesterol metabolism - Homo sapiens (human)
  • Vesicle-mediated transport
  • Membrane Trafficking
  • Chylomicron clearance

Biological Process

  • receptor-mediated endocytosis
  • cholesterol metabolic process
  • positive regulation of signal transduction
  • cholesterol transport
  • receptor internalization

Molecular Function

  • amyloid-beta binding
  • phosphotyrosine residue binding
  • protein binding
  • phosphatidylinositol-4,5-bisphosphate binding
  • receptor signaling complex scaffold activity

Cellular Component

  • early endosome
  • cytosol
  • neurofilament
  • plasma membrane
  • cytoplasmic side of plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000374338
Coding exons
9
Length
25307
Individuals with no LoFs
125719
Homozygous LoFs
0
Heterozygous LoFs
29
Defined
125748
p
0.000115
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.2011741671.040.00001022008
Missense (PolyPhen)4644.8221.0263485
Synonymous0.2327476.60.9660.00000556600
Loss of Function1.111014.60.6866.34e-7184

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000370.00018rare
Latino/Admixed American0.000120.00012rare
Ashkenazi Jewish00.0absent
East Asian0.000110.00011rare
Finnish0.0000480.000046rare
European (Non-Finnish)0.000130.00013rare
South Asian0.000130.00013rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Adapter protein (clathrin-associated sorting protein (CLASP)) required for efficient endocytosis of the LDL receptor (LDLR) in polarized cells such as hepatocytes and lymphocytes, but not in non-polarized cells (fibroblasts). May be required for LDL binding and internalization but not for receptor clustering in coated pits. May facilitate the endocytocis of LDLR and LDLR-LDL complexes from coated pits by stabilizing the interaction between the receptor and the structural components of the pits. May also be involved in the internalization of other LDLR family members. Binds to phosphoinositides, which regulate clathrin bud assembly at the cell surface. Required for trafficking of LRP2 to the endocytic recycling compartment which is necessary for LRP2 proteolysis, releasing a tail fragment which translocates to the nucleus and mediates transcriptional repression (By similarity). {ECO:0000250|UniProtKB:D3ZAR1, ECO:0000269|PubMed:15728179}.;
Disease
DISEASE: Hypercholesterolemia, autosomal recessive (ARH) [MIM:603813]: A familial condition characterized by elevated circulating cholesterol contained in either low-density lipoproteins alone or also in very-low-density lipoproteins. {ECO:0000269|PubMed:11326085}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.425

Intolerance Scores

LoFtool
0.699
RVIS EVS
0.37
RVIS percentile EVS
75.29

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.616

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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