LDLRAP1

low density lipoprotein receptor adaptor protein 1

Basic information

Region (hg38): 1:25543604-25591200

Links

ENSG00000157978 ∙ NCBI:26119 ∙ OMIM:605747 ∙ HGNC:18640 ∙ Uniprot:Q5SW96 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• hypercholesterolemia, familial, 4 (Strong), mode of inheritance: AR
• hypercholesterolemia, familial, 4 (Strong), mode of inheritance: AR
• homozygous familial hypercholesterolemia (Supportive), mode of inheritance: AR
• hypercholesterolemia, familial, 4 (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Hypercholesterolemia, familial, 4	AR	Cardiovascular	Interventions to maintain lipid profiles at a more desirable level can decrease morbidity/mortality, such as relates to CAD	Cardiovascular; Dermatologic	11326085; 15599766; 21872251

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the LDLRAP1 gene.

• Hypercholesterolemia, familial, 4 (29 variants)
• not provided (4 variants)
• Familial hypercholesterolemia (4 variants)
• Cardiovascular phenotype (3 variants)
• Autosomal recessive inheritance (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the LDLRAP1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				150	1	151
missense			112	7	2	121
nonsense	13	1	1			15
start loss		1				1
frameshift	18	5				23
inframe indel						0
splice donor/acceptor (+/-2bp)	2	9				11
splice region			6	37	2	45
non coding		1	45	76	14	136
Total	33	17	158	233	17

Highest pathogenic variant AF is 0.0000133

Variants in LDLRAP1

This is a list of pathogenic ClinVar variants found in the LDLRAP1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
1-25543607-G-T		Hypercholesterolemia, familial, 4	Uncertain significance (Jan 12, 2018)
1-25543619-C-A		Hypercholesterolemia, familial, 4	Conflicting classifications of pathogenicity (Dec 21, 2023)
1-25543624-G-T		Hypercholesterolemia, familial, 4	Uncertain significance (Apr 27, 2017)
1-25543629-A-T		Hypercholesterolemia, familial, 4	Uncertain significance (Jan 12, 2018)
1-25543631-G-A		Hypercholesterolemia, familial, 4	Uncertain significance (Apr 11, 2023)
1-25543640-G-A		Hypercholesterolemia, familial, 4	Uncertain significance (Jan 12, 2018)
1-25543653-G-C		Hypercholesterolemia, familial, 4	Benign (Mar 31, 2023)
1-25543662-T-C		Hypercholesterolemia, familial, 4	Uncertain significance (Jan 13, 2018)
1-25543670-G-C		LDLRAP1-related disorder	Likely benign (May 03, 2021)
1-25543689-G-A		not specified	Uncertain significance (Aug 12, 2024)
1-25543699-A-G		Hypercholesterolemia, familial, 4	Likely pathogenic (Nov 15, 2022)
1-25543704-C-T		Hypercholesterolemia, familial, 4 • Cardiovascular phenotype	Likely benign (Jan 14, 2024)
1-25543707-G-A		Hypercholesterolemia, familial, 4	Likely benign (Nov 13, 2023)
1-25543707-G-T		Hypercholesterolemia, familial, 4	Likely benign (Sep 08, 2023)
1-25543708-C-T		Cardiovascular phenotype	Uncertain significance (Mar 30, 2022)
1-25543710-C-T		Hypercholesterolemia, familial, 4 • Cardiovascular phenotype	Likely benign (May 17, 2024)
1-25543715-C-A		Hypercholesterolemia, familial, 4	Pathogenic (Nov 20, 2023)
1-25543716-G-A		Hypercholesterolemia, familial, 4	Likely benign (Dec 18, 2021)
1-25543716-G-T		Hypercholesterolemia, familial, 4	Likely benign (Apr 25, 2022)
1-25543717-GC-G		Hypercholesterolemia, familial, 4	Pathogenic (Apr 17, 2021)
1-25543718-C-CG		Cardiovascular phenotype	Pathogenic (May 07, 2020)
1-25543719-G-A		Hypercholesterolemia, familial, 4 • Cardiovascular phenotype • LDLRAP1-related disorder	Likely benign (Jan 25, 2024)
1-25543719-G-C		Hypercholesterolemia, familial, 4	Likely benign (Nov 18, 2021)
1-25543719-G-T		Hypercholesterolemia, familial, 4	Likely benign (Sep 19, 2023)
1-25543722-G-A		Hypercholesterolemia, familial, 4 • Cardiovascular phenotype	Likely benign (Apr 11, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
LDLRAP1	protein_coding	protein_coding	ENST00000374338	9	25307

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00000650	0.722	125719	0	29	125748	0.000115

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.201	174	167	1.04	0.0000102	2008
Missense in Polyphen		46	44.822	1.0263		485
Synonymous	0.232	74	76.6	0.966	0.00000556	600
Loss of Function	1.11	10	14.6	0.686	6.34e-7	184

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000486	0.000300
Ashkenazi Jewish	0.00	0.00
East Asian	0.000109	0.000109
Finnish	0.0000475	0.0000462
European (Non-Finnish)	0.000132	0.000132
Middle Eastern	0.000109	0.000109
South Asian	0.000131	0.000131
Other	0.00	0.00

dbNSFP

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.
• Pathway: Endocytosis - Homo sapiens (human);Cholesterol metabolism - Homo sapiens (human);Vesicle-mediated transport;Membrane Trafficking;Chylomicron clearance;LDL clearance;Plasma lipoprotein clearance;Transport of small molecules;Clathrin-mediated endocytosis;Plasma lipoprotein assembly, remodeling, and clearance;Cargo recognition for clathrin-mediated endocytosis (Consensus)

Recessive Scores

• pRec: 0.425

Intolerance Scores

• loftool: 0.699
• rvis_EVS: 0.37
• rvis_percentile_EVS: 75.29

Haploinsufficiency Scores

• pHI: 0.217
• hipred: Y
• hipred_score: 0.728
• ghis: 0.443

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.616

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Ldlrap1
• Phenotype: homeostasis/metabolism phenotype

Gene ontology

• Biological process: receptor-mediated endocytosis;cholesterol metabolic process;positive regulation of signal transduction;cholesterol transport;receptor internalization;low-density lipoprotein particle clearance;cholesterol homeostasis;amyloid precursor protein metabolic process;regulation of protein binding;positive regulation of receptor-mediated endocytosis;membrane organization;cellular response to cytokine stimulus;receptor-mediated endocytosis involved in cholesterol transport;positive regulation of cholesterol metabolic process;regulation of protein localization to plasma membrane;positive regulation of vascular smooth muscle cell proliferation;positive regulation of low-density lipoprotein particle clearance;positive regulation of receptor-mediated endocytosis involved in cholesterol transport
• Cellular component: early endosome;cytosol;neurofilament;plasma membrane;cytoplasmic side of plasma membrane;basal plasma membrane;axon;clathrin-coated vesicle membrane;recycling endosome
• Molecular function: amyloid-beta binding;phosphotyrosine residue binding;protein binding;phosphatidylinositol-4,5-bisphosphate binding;receptor signaling complex scaffold activity;clathrin binding;signaling adaptor activity;AP-2 adaptor complex binding;clathrin adaptor activity;AP-1 adaptor complex binding;low-density lipoprotein particle receptor binding