Human Gene Module / Chromosome 10 / SORCS3

SORCS3sortilin related VPS10 domain containing receptor 3

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
3 / 7
Rare Variants / Common Variants
2 / 5
Aliases
SORCS3, SORCS
Associated Syndromes
-
Chromosome Band
10q25.1
Associated Disorders
-
Relevance to Autism

A cross-trait meta-analysis of genome-wide association studies on schizophrenia (65,967 cases), bipolar disorder (41,653 cases), autism spectrum disorder (46,350 cases), ADHD (55,374 cases) and depression (688,809 cases) identified an intronic SNP in the SORCS3 gene that reached genome-wide significance for ASD following MTAG analysis (P-value 6.26E-09) (Wu et al., 2020). Other SNPs in this gene have previously been shown to reach genome-wide significance for association with ADHD (Demontis et al., 2018) and depression (Wray et al., 2018; Howard et al., 2019). A de novo nonsense variant in SORCS3 was identified in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014), and a homozygous missense variant in this gene was identified in two deceased brothers born to consanguineous parents who had presented with global developmental delay, intellectual disability, infantile spasms, microcephaly, and hypotonia (Alfadhel et al., 2018).

Molecular Function

This gene encodes a type-I receptor transmembrane protein that is a member of the vacuolar protein sorting 10 receptor family. Proteins of this family are defined by a vacuolar protein sorting 10 domain at the N-terminus. The N-terminal segment of this domain has a consensus motif for proprotein convertase processing, and the C-terminal segment of this domain is characterized by ten conserved cysteine residues. The vacuolar protein sorting 10 domain is followed by a leucine-rich segment, a transmembrane domain, and a short C-terminal cytoplasmic domain that interacts with adaptor molecules. The transcript is expressed at high levels in the brain, and candidate gene studies suggest that genetic variation in this gene is associated with Alzheimer's disease. Consistent with this observation, knockdown of the gene in cell culture results in an increase in amyloid precursor protein processing.

External Links
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Human
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SFARI Genomic Platforms
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Reports related to SORCS3 (7 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
2 Positive Association Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression Wray NR , et al. (2018) No -
3 Positive Association Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder Demontis D , et al. (2018) No -
4 Support The SORCS3 gene is mutated in brothers with infantile spasms and intellectual disability Alfadhel M et al. (2018) No -
5 Positive Association Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions Howard DM et al. (2019) No -
6 Primary Multi-trait analysis for genome-wide association study of five psychiatric disorders Wu Y et al. (2020) Yes -
7 Positive Association - Yi Yang et al. () Yes -
Rare Variants   (2)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.2938C>T p.Gln980Ter stop_gained De novo - - 25363760 De Rubeis S , et al. (2014)
c.3110C>G p.Thr1037Ser missense_variant Familial Both parents Multiplex 30586538 Alfadhel M et al. (2018)
Common Variants   (5)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
- - intron_variant - - - 38821058 Yi Yang et al. ()
c.954+7853T>G - intron_variant - - - 32606422 Wu Y et al. (2020)
c.628-38626C>T - intron_variant - - - 29700475 Wray NR , et al. (2018)
c.695+8222A>G - intron_variant - - - 30718901 Howard DM et al. (2019)
c.954+10103T>A - intron_variant - - - 30478444 Demontis D , et al. (2018)
SFARI Gene score
2

Strong Candidate

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

4/1/2022
icon
2

Increased from to 2

Krishnan Probability Score

Score 0.6033041800115

Ranking 366/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.32513426350828

Ranking 6369/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.51179727631057

Ranking 474/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score 0.20872764826425

Ranking 4137/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
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