VLDLR

protein-coding

very low density lipoprotein receptor, the group of Low density lipoprotein receptors

Gene summary

The low density lipoprotein receptor (LDLR) gene family consists of cell surface proteins involved in receptor-mediated endocytosis of specific ligands. This gene encodes a lipoprotein receptor that is a member of the LDLR family and plays important roles in VLDL-triglyceride metabolism and the reelin signaling pathway. Mutations in this gene cause VLDLR-associated cerebellar hypoplasia. Alternative splicing generates multiple transcript variants encoding distinct isoforms for this gene. [provided by RefSeq, Aug 2009]

MANE transcript

NM_003383.5

Inheritance

ClinVar variants

P:63U:200B:259

Top phenotype

Cerebellar hypoplasia, impaired intellectual development, and dysequilibrium syndrome 1

gnomAD constraint

pLI —, LoF o/e 0.52

Max pathogenic AF

—

Genomic locus

chr9:2,621,182-2,660,056

External References & Databases

Ensembl (ENSG00000147852)

Transcript & Mutation Effects

hg38 • Region Span ~38.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0024542

Submitter: G2P

cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0024542

Submitter: Labcorp Genetics (formerly Invitae)

cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0024542

Submitter: ClinGen

VLDLR was first reported in relation to autosomal recessive cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 1 (CAMRQ1) in 2005 (Boycott et al., PMID: 16080122). CAMRQ1 due to VLDLR variants is characterized by non-progressive congenital ataxia that is predominantly truncal and results in delayed ambulation, moderate-to-profound intellectual disability, dysarthria, strabismus, and seizures. At the time of this curation, there were no other single-gene disorders associated with this gene. This curation is based on this disease entity only. Eleven variants (missense, nonsense, splice, frameshift) that have been reported in 8 probands across 5 publications (PMIDs: 18326629, 27000652, 19332571, 22532556, 22700954) are included in this curation. The mechanism of pathogenicity is reported to be loss of function. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is also supported by expression studies and an animal model (PMIDs: 25668033, 19393635, 10380922). In summary, VLDLR is definitively associated with autosomal recessive cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 1. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Brain Malformations Gene Curation Expert Panel on the meeting date 06/13/23 (SOP Version 9).

cerebellar ataxia, intellectual disability, and dysequilibriumSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009133

Submitter: Orphanet

cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0024542

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Cerebellar hypoplasia, impaired intellectual development, and dysequilibrium syndrome 1AR

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 16080122; 18043714; 18326629; 18364738; 20082205

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to VLDLR variants in ClinVar

11 Conditions Cataloged

not providedTotal: 613

Inborn genetic diseasesTotal: 121

Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 1Total: 107

not specifiedTotal: 61

VLDLR-related disorderTotal: 23

Intellectual disabilityTotal: 3

Dysequilibrium syndromeTotal: 2

See casesTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003383.5. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			7 clinvar	242 clinvar	1 clinvar	250
missense	2 clinvar	3 clinvar	188 clinvar	16 clinvar		209
nonsense	18 clinvar	5 clinvar				23
start loss		1 clinvar				1
frameshift	11 clinvar	3 clinvar	1 clinvar			15
splice donor/acceptor (+/-2bp)	1 clinvar	19 clinvar	4 clinvar			24
Total	32	31	200	258	1	522

Highest pathogenic variant AF is 0.000016108486

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 43 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003383.5	RefSeq	NP_003374.3	19	MANE Select
ENST00000382100.8	Ensembl	ENSP00000371532.2	19	MANE Select
NM_001018056.3	RefSeq	NP_001018066.1	18	Standard
NM_001322225.2	RefSeq	NP_001309154.1	18	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Developmental Biology
VLDL clearance
VLDLR internalisation and degradation
Plasma lipoprotein clearance
Transport of small molecules

Biological Process

negative regulation of transcription by RNA polymerase II
lipid transport
receptor-mediated endocytosis
signal transduction
nervous system development

Molecular Function

low-density lipoprotein particle receptor activity
calcium ion binding
protein binding
very-low-density lipoprotein particle receptor activity
apolipoprotein binding

Cellular Component

lysosomal membrane
plasma membrane
clathrin-coated pit
membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000382100
Coding exons: 19
Length: 38220
Individuals with no LoFs: 125698
Homozygous LoFs: 0
Heterozygous LoFs: 50
Defined: 125748
p: 0.000199

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-1.12	534	466	1.15	0.0000262	5813
Missense (PolyPhen)		161	186.32	0.86411		2403
Synonymous	-1.74	203	174	1.17	0.0000107	1567
Loss of Function	3.17	26	50.3	0.517	0.00000323	557

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00049	0.00049	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0.00089	0.00089	rare
East Asian	0.00033	0.00033	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00020	0.00020	rare
South Asian	0.000065	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Binds VLDL and transports it into cells by endocytosis. In order to be internalized, the receptor-ligand complexes must first cluster into clathrin-coated pits. Binding to Reelin induces tyrosine phosphorylation of Dab1 and modulation of Tau phosphorylation (By similarity). {ECO:0000250}.;
Disease: DISEASE: Cerebellar ataxia, mental retardation, and dysequilibrium syndrome 1 (CAMRQ1) [MIM:224050]: A congenital, non-progressive cerebellar ataxia associated with disturbed equilibrium, delayed ambulation, mental retardation, cerebellar hypoplasia and mild cerebral gyral simplification. Additional features include short stature, strabismus, pes planus and, rarely, seizures. {ECO:0000269|PubMed:16080122}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.490

Intolerance Scores

LoFtool: 0.0391
RVIS EVS: -1.06
RVIS percentile EVS: 7.55

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.690

Gene Damage Prediction

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