SORL1

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

Basic information

Region (hg38): 11:121452314-121633763

Previous symbols: [ "C11orf32" ]

Links

ENSG00000137642 ∙ NCBI:6653 ∙ OMIM:602005 ∙ HGNC:11185 ∙ Uniprot:Q92673 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• early-onset autosomal dominant Alzheimer disease (Supportive), mode of inheritance: AD

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SORL1 gene.

• not_provided (649 variants)
• not_specified (243 variants)
• SORL1-related_disorder (25 variants)
• Early-onset_dementia_of_unclear_type (1 variants)
• Moyamoya_angiopathy (1 variants)
• Complex_hereditary_spastic_paraplegia (1 variants)
• Alzheimer_disease_9 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SORL1 gene is commonly pathogenic or not. These statistics are base on transcript: NM_000003105.6. Only rare variants are included in the table.

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.

Effect	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			4	123	27	154
missense		1	469	47	12	529
nonsense	7					7
start loss						0
frameshift	7		1			8
splice donor/acceptor (+/-2bp)	1	3				4
Total	15	4	474	170	39

Highest pathogenic variant AF is 0.000008058917

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SORL1	protein_coding	protein_coding	ENST00000260197	48	181491

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
7.66e-11	1.00	125655	0	93	125748	0.000370

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.03	1068	1.27e+3	0.840	0.0000738	14657
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000762	0.000762
Ashkenazi Jewish	0.000298	0.000298
East Asian	0.000273	0.000272
Finnish	0.000237	0.000231
European (Non-Finnish)	0.000479	0.000466
Middle Eastern	0.000273	0.000272
South Asian	0.000163	0.000163
Other	0.000654	0.000652

dbNSFP

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.
• Pathway: Metabolism of proteins;Amyloid fiber formation (Consensus)

Intolerance Scores

• loftool: 0.0875
• rvis_EVS: -2.34
• rvis_percentile_EVS: 1.16

Haploinsufficiency Scores

• pHI: 0.802
• hipred: N
• hipred_score: 0.476
• ghis: 0.554

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.882

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Sorl1
• Phenotype: nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); muscle phenotype; homeostasis/metabolism phenotype

Gene ontology

• Biological process: protein targeting;protein targeting to lysosome;lipid transport;post-Golgi vesicle-mediated transport;receptor-mediated endocytosis;cholesterol metabolic process;regulation of smooth muscle cell migration;negative regulation of protein binding;negative regulation of protein oligomerization;protein localization to Golgi apparatus;negative regulation of MAP kinase activity;cellular protein metabolic process;protein retention in Golgi apparatus;positive regulation of protein catabolic process;negative regulation of neurogenesis;protein maturation;positive regulation of protein exit from endoplasmic reticulum;negative regulation of neuron death;negative regulation of amyloid-beta formation;positive regulation of choline O-acetyltransferase activity;negative regulation of tau-protein kinase activity;positive regulation of ER to Golgi vesicle-mediated transport;positive regulation of early endosome to recycling endosome transport;negative regulation of aspartic-type endopeptidase activity involved in amyloid precursor protein catabolic process;negative regulation of metalloendopeptidase activity involved in amyloid precursor protein catabolic process;positive regulation of protein localization to early endosome;negative regulation of neurofibrillary tangle assembly;positive regulation of endocytic recycling
• Cellular component: Golgi membrane;extracellular space;nuclear envelope lumen;endosome;early endosome;endoplasmic reticulum;Golgi apparatus;trans-Golgi network;integral component of plasma membrane;endosome membrane;membrane;Golgi cisterna;low-density lipoprotein particle;recycling endosome;extracellular exosome
• Molecular function: amyloid-beta binding;transmembrane signaling receptor activity;low-density lipoprotein particle receptor activity;protein binding;low-density lipoprotein particle binding;ADP-ribosylation factor binding