Human Gene Module / Chromosome 11 / PACS1

PACS1phosphofurin acidic cluster sorting protein 1

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
6 / 20
Rare Variants / Common Variants
21 / 0
EAGLE Score
1.35
Limited Learn More
Aliases
PACS1, MRD17
Associated Syndromes
Schuurs-Hoeijmakers syndrome, DD, ID, Schuurs-Hoeijmakers syndrome
Chromosome Band
11q13.1-q13.2
Associated Disorders
EP, ASD, EPS
Genetic Category
Rare Single Gene Mutation, Syndromic, Functional
Relevance to Autism

Clinical evaluation of 19 patients with a syndromic form of intellectual disability resulting from a recurrent de novo missense variant in the PACS1 gene (p.Arg203Trp) demonstrated that 6/19 individuals presented with ASD or showed behavior with the autism spectrum (Schuurs-Hoeijmakers et al., 2016). Functional characterization of the p.Arg203Trp variant showed that expression of mutant PACS1 mRNA in zebrafish embryos induced craniofacial defects (Schuurs-Hoeijmakers et al., 2012).

Molecular Function

This gene encodes a protein with a putative role in the localization of trans-Golgi network (TGN) membrane proteins that contain acidic cluster sorting motifs. Controls the endosome-to-Golgi trafficking of furin and mannose-6-phosphate receptor by connecting the acidic-cluster-containing cytoplasmic domain of these molecules with the adapter-protein complex-1 (AP-1) of endosomal clathrin-coated membrane pits.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Zebrafish
Entrez Gene
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to PACS1 (20 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Recurrent de novo mutations in PACS1 cause defective cranial-neural-crest migration and define a recognizable intellectual-disability syndrome Schuurs-Hoeijmakers JH , et al. (2012) No -
2 Primary Clinical delineation of the PACS1-related syndrome--Report on 19 patients Schuurs-Hoeijmakers JH , et al. (2016) No ASD
3 Support Association of the missense variant p.Arg203Trp in PACS1 as a cause of intellectual disability and seizures Stern D , et al. (2017) No Epilepsy/seizures, ASD
4 Support Genomic diagnosis for children with intellectual disability and/or developmental delay Bowling KM , et al. (2017) No -
5 Support Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains Geisheker MR , et al. (2017) Yes -
6 Support Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder Lim ET , et al. (2017) Yes -
7 Support - Tenorio-Castaño J et al. (2021) No ASD, epilepsy/seizures, stereotypy
8 Recent Recommendation - Van Nuland A et al. (2021) No ASD, epilepsy/seizures
9 Support - Pode-Shakked B et al. (2021) Yes -
10 Support - et al. () No -
11 Support - Bruno LP et al. (2021) No Stereotypy
12 Support - Li D et al. (2022) Yes -
13 Support - Chen Y et al. (2021) No -
14 Support - Zhou X et al. (2022) Yes -
15 Support - Moller-Hansen A et al. (2023) No SAD, depression
16 Support - Cirnigliaro M et al. (2023) Yes -
17 Support - et al. () No -
18 Support - et al. () No -
19 Support - et al. () No -
20 Support - et al. () No -
Rare Variants   (21)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.607C>T p.Arg203Trp missense_variant Unknown - - 38438125 et al. ()
c.115C>T p.Gln39Ter stop_gained Unknown - - 34968013 Li D et al. (2022)
c.607C>T p.Arg203Trp missense_variant Unknown - Simplex 37799141 et al. ()
c.607C>T p.Arg203Trp missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.607C>T p.Arg203Trp missense_variant De novo - - 28111752 Stern D , et al. (2017)
c.1545G>A p.Glu515%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.119_121dup p.Gln40dup inframe_insertion De novo - - 35982159 Zhou X et al. (2022)
c.607C>T p.Arg203Trp missense_variant Unknown - - 28554332 Bowling KM , et al. (2017)
c.607C>T p.Arg203Trp missense_variant De novo - Simplex 35873028 Chen Y et al. (2021)
c.607C>T p.Arg203Trp missense_variant De novo - - 28628100 Geisheker MR , et al. (2017)
c.607C>T p.Arg203Trp missense_variant Unknown - - 28628100 Geisheker MR , et al. (2017)
c.2126G>A p.Arg709Gln missense_variant De novo - Simplex 28714951 Lim ET , et al. (2017)
c.607C>T p.Arg203Trp missense_variant De novo - Simplex 34948243 Bruno LP et al. (2021)
c.1545G>A p.Glu515%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1622C>T p.Thr541Met missense_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.607C>T p.Arg203Trp missense_variant De novo - - 34068396 Tenorio-Castaño J et al. (2021)
c.607C>T p.Arg203Trp missense_variant De novo - Simplex 34580403 Pode-Shakked B et al. (2021)
c.607C>T p.Arg203Trp missense_variant De novo - - 26842493 Schuurs-Hoeijmakers JH , et al. (2016)
c.560C>T p.Ala187Val missense_variant Familial Paternal Simplex 28628100 Geisheker MR , et al. (2017)
c.755C>T p.Ser252Phe missense_variant Familial Maternal Simplex 37141437 Moller-Hansen A et al. (2023)
c.135_136del p.Thr46AlafsTer73 frameshift_variant Familial Maternal Multiplex 37506195 Cirnigliaro M et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
1S

High Confidence, Syndromic

Score Delta: Score remained at 1S

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 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.

S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

4/1/2021
1
icon
1

Score remained at 1

Description

Clinical evaluation of 19 patients with a syndromic form of intellectual disability resulting from a recurrent de novo missense variant in the PACS1 gene (p.Arg203Trp) demonstrated that 6/19 individuals presented with ASD or showed behavior with the autism spectrum (Schuurs-Hoeijmakers et al., 2016). Functional characterization of the p.Arg203Trp variant showed that expression of mutant PACS1 mRNA in zebrafish embryos induced craniofacial defects (Schuurs-Hoeijmakers et al., 2012). Eight additional patients with developmental delay/intellectual disability resulting from the recurrent de novo p.Arg203Trp variant in the PACS1 gene were reported by Stern et al., 2017; autism was diagnosed in two of these patients.

Reports Added
[Schuurs-Hoeijmakers Syndrome ( PACS1 Neurodevelopmental Disorder): Seven Novel Patients and a Review2021]
10/1/2019
S
icon
1

Increased from S to 1

New Scoring Scheme
Description

Clinical evaluation of 19 patients with a syndromic form of intellectual disability resulting from a recurrent de novo missense variant in the PACS1 gene (p.Arg203Trp) demonstrated that 6/19 individuals presented with ASD or showed behavior with the autism spectrum (Schuurs-Hoeijmakers et al., 2016). Functional characterization of the p.Arg203Trp variant showed that expression of mutant PACS1 mRNA in zebrafish embryos induced craniofacial defects (Schuurs-Hoeijmakers et al., 2012). Eight additional patients with developmental delay/intellectual disability resulting from the recurrent de novo p.Arg203Trp variant in the PACS1 gene were reported by Stern et al., 2017; autism was diagnosed in two of these patients.

Reports Added
[New Scoring Scheme]
7/1/2017
S
icon
S

Increased from S to S

Description

Clinical evaluation of 19 patients with a syndromic form of intellectual disability resulting from a recurrent de novo missense variant in the PACS1 gene (p.Arg203Trp) demonstrated that 6/19 individuals presented with ASD or showed behavior with the autism spectrum (Schuurs-Hoeijmakers et al., 2016). Functional characterization of the p.Arg203Trp variant showed that expression of mutant PACS1 mRNA in zebrafish embryos induced craniofacial defects (Schuurs-Hoeijmakers et al., 2012). Eight additional patients with developmental delay/intellectual disability resulting from the recurrent de novo p.Arg203Trp variant in the PACS1 gene were reported by Stern et al., 2017; autism was diagnosed in two of these patients.

Reports Added
[Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains.2017] [Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder.2017]
4/1/2017
S
icon
S

Increased from S to S

Description

Clinical evaluation of 19 patients with a syndromic form of intellectual disability resulting from a recurrent de novo missense variant in the PACS1 gene (p.Arg203Trp) demonstrated that 6/19 individuals presented with ASD or showed behavior with the autism spectrum (Schuurs-Hoeijmakers et al., 2016). Functional characterization of the p.Arg203Trp variant showed that expression of mutant PACS1 mRNA in zebrafish embryos induced craniofacial defects (Schuurs-Hoeijmakers et al., 2012). Eight additional patients with developmental delay/intellectual disability resulting from the recurrent de novo p.Arg203Trp variant in the PACS1 gene were reported by Stern et al., 2017; autism was diagnosed in two of these patients.

Reports Added
[Clinical delineation of the PACS1-related syndrome-Report on 19 patients.2016] [Recurrent de novo mutations in PACS1 cause defective cranial-neural-crest migration and define a recognizable intellectual-disability syndrome.2012] [Association of the missense variant p.Arg203Trp in PACS1 as a cause of intellectual disability and seizures.2017] [Genomic diagnosis for children with intellectual disability and/or developmental delay.2017]
Krishnan Probability Score

Score 0.44727861047867

Ranking 13124/25841 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 0.99990635168519

Ranking 668/18225 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 0.94333034577955

Ranking 15646/18665 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 0.38981897842378

Ranking 1565/20870 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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