SORL1

protein-coding

sortilin related receptor 1, the group of Fibronectin type III domain containing

Gene summary

This gene encodes a mosaic protein that belongs to at least two families: the vacuolar protein sorting 10 (VPS10) domain-containing receptor family, and the low density lipoprotein receptor (LDLR) family. The encoded protein also contains fibronectin type III repeats and an epidermal growth factor repeat. The encoded preproprotein is proteolytically processed to generate the mature receptor, which likely plays roles in endocytosis and sorting. Mutations in this gene may be associated with Alzheimer's disease. [provided by RefSeq, Feb 2016]

Previous symbols:

C11orf32

MANE transcript

NM_003105.6

Inheritance

ClinVar variants

P:29U:577B:234

Top phenotype

early-onset autosomal dominant Alzheimer disease

gnomAD constraint

pLI —, LoF o/e 0.34

Max pathogenic AF

—

Genomic locus

chr11:121,452,314-121,633,763

External References & Databases

Ensembl (ENSG00000137642)

Transcript & Mutation Effects

hg38 • Region Span ~181.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

early-onset autosomal dominant Alzheimer diseaseSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015140

Submitter: Orphanet

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SORL1 variants in ClinVar

7 Conditions Cataloged

not providedTotal: 739

not specifiedTotal: 282

SORL1-related disorderTotal: 25

Early-onset dementia of unclear typeTotal: 1

Moyamoya angiopathyTotal: 1

Complex hereditary spastic paraplegiaTotal: 1

Alzheimer disease 9Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003105.6. 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		1 clinvar	10 clinvar	144 clinvar	28 clinvar	183
missense		1 clinvar	547 clinvar	50 clinvar	12 clinvar	610
nonsense	10 clinvar		1 clinvar			11
start loss						0
frameshift	8 clinvar	2 clinvar	1 clinvar			11
splice donor/acceptor (+/-2bp)	1 clinvar	6 clinvar	18 clinvar			25
Total	19	10	577	194	40	840

Highest pathogenic variant AF is 0.000010261448

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 23 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003105.6	RefSeq	NP_003096.2	48	MANE Select
ENST00000260197.12	Ensembl	ENSP00000260197.6	48	MANE Select
ENST00000525532.5	Ensembl	ENSP00000434634.1	27	Standard
ENST00000525532.6	Ensembl	ENSP00000434634.1	27	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Metabolism of proteins
Amyloid fiber formation

Biological Process

protein targeting
protein targeting to lysosome
lipid transport
post-Golgi vesicle-mediated transport
receptor-mediated endocytosis

Molecular Function

amyloid-beta binding
transmembrane signaling receptor activity
low-density lipoprotein particle receptor activity
protein binding
low-density lipoprotein particle binding

Cellular Component

Golgi membrane
extracellular space
nuclear envelope lumen
endosome
early endosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000260197
Coding exons: 48
Length: 181491
Individuals with no LoFs: 125655
Homozygous LoFs: 0
Heterozygous LoFs: 93
Defined: 125748
p: 0.000370

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.03	1068	1.27e+3	0.840	0.0000738	14657
Missense (PolyPhen)		388	533.62	0.72711		6113
Synonymous	0.855	478	502	0.951	0.0000320	4109
Loss of Function	6.85	42	124	0.337	0.00000672	1379

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00043	0.00043	rare
Latino/Admixed American	0.00033	0.00032	rare
Ashkenazi Jewish	0.00030	0.00030	rare
East Asian	0.00027	0.00027	rare
Finnish	0.00024	0.00023	rare
European (Non-Finnish)	0.00048	0.00047	rare
South Asian	0.00016	0.00016	rare
Other	0.00065	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Likely to be a multifunctional endocytic receptor, that may be implicated in the uptake of lipoproteins and of proteases. Binds LDL, the major cholesterol-carrying lipoprotein of plasma, and transports it into cells by endocytosis. Binds the receptor- associated protein (RAP). Could play a role in cell-cell interaction. Involved in APP trafficking to and from the Golgi apparatus. It probably acts as a sorting receptor that protects APP from trafficking to late endosome and from processing into amyloid beta, thereby reducing the burden of amyloidogenic peptide formation. Involved in the regulation of smooth muscle cells migration, probably through PLAUR binding and decreased internalization. {ECO:0000269|PubMed:14764453, ECO:0000269|PubMed:16174740}.;
Disease: DISEASE: Alzheimer disease (AD) [MIM:104300]: Alzheimer disease is a neurodegenerative disorder characterized by progressive dementia, loss of cognitive abilities, and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles, extracellular amyloid plaques and vascular amyloid deposits. The major constituents of these plaques are neurotoxic amyloid-beta protein 40 and amyloid-beta protein 42, that are produced by the proteolysis of the transmembrane APP protein. The cytotoxic C- terminal fragments (CTFs) and the caspase-cleaved products, such as C31, are also implicated in neuronal death. {ECO:0000269|PubMed:21220680, ECO:0000269|PubMed:22472873, ECO:0000269|PubMed:23565137}. Note=The gene represented in this entry is involved in disease pathogenesis.;

Intolerance Scores

LoFtool: 0.0875
RVIS EVS: -2.34
RVIS percentile EVS: 1.16

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.882

Gene Damage Prediction

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