PACS1

protein-coding

phosphofurin acidic cluster sorting protein 1

Gene summary

This gene encodes a protein with a putative role in the localization of trans-Golgi network (TGN) membrane proteins. Mouse and rat homologs have been identified and studies of the homologous rat protein indicate a role in directing TGN localization of furin by binding to the protease's phosphorylated cytosolic domain. In addition, the human protein plays a role in HIV-1 Nef-mediated downregulation of cell surface MHC-I molecules to the TGN, thereby enabling HIV-1 to escape immune surveillance. [provided by RefSeq, Jul 2008]

MANE transcript

NM_018026.4

Inheritance

ClinVar variants

P:5U:368B:338

Top phenotype

Schuss-Hoeijmakers syndrome

gnomAD constraint

pLI —, LoF o/e 0.08

Max pathogenic AF

—

Genomic locus

chr11:66,070,272-66,244,744

External References & Databases

Ensembl (ENSG00000175115)

Transcript & Mutation Effects

hg38 • Region Span ~174.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Schuurs-Hoeijmakers syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014006

Submitter: ClinGen

*PACS1* was first reported in relation to autosomal dominant Schuurs-Hoeijmakers syndrome in 2012 (Schuurs-Hoeijmakers et al., PMID: 23159249). At least 2 unique missense variants (NM_018026.4:c.607C>T, p.Arg203Trp and c.608G>A, p.Arg203Gln) have been reported in humans. All but one reported cases are due to the p.Arg203Trp mutation. Miyake et al. (2018, PMID: 28975623) reported the first and only case of p.Arg203Gln and described the same distinctive facial dysmorphisms characteristic of the Schuurs-Hoeijmakers syndrome. These features typically include full, arched eyebrows, hypertelorism, down-slanting palpebral fissures, long eyelashes, ptosis, low-set, large ears, bulbous tip of nose, flat philtrum, wide mouth with downturned corners and thin upper lip with a wavy profile, and diastema of the teeth. Other common phenotypes include intellectual disability, delayed speech development, cryptorchidism in males, seizures, hypotonia, and congenital anomalies affecting the heart, brain, or eyes. Variants in this gene have been reported in at least 33 probands in nine publications (PMIDs: 23159249, 25522177, 26842493, 28111752, 28975623, 29550517, 30113927, 30588754, 30690871). Among these, six probands from four publications (PMIDs: 23159249, 25522177, 28975623, 30588754) were selected to be scored based on confirmed *de novo* status, representation of the variant spectrum, diversity in ethnic groups, and variant detection via trio-based exome sequencing. This gene-disease relationship is also supported by *in vivo* functional assays in a non-human model organism. To understand the mechanistic basis of the human dysmorphic phenotype, Schuurs-Hoeijmakers et al. (2012, PMID: 23159249) studied the effect of the p.Arg203Trp substitution in craniofacial cartilaginous structures in zebrafish embryos and found that the expression of mutant *PACS1* mRNA in zebrafish embryos induces craniofacial defects most likely in a dominant-negative fashion and that this phenotype is driven by aberrant specification and migration of SOX10-positive cranial, but not enteric, neural-crest cells. In summary, *PACS1* is definitively associated with autosomal dominant Schuurs-Hoeijmakers syndrome, also known as intellectual disability-craniofacial dysmorphism-cryptorchidism syndrome. 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 Intellectual Disability and Autism Gene Curation Expert Panel on June 26, 2020 (SOP Version 7).

Schuurs-Hoeijmakers syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014006

Submitter: Labcorp Genetics (formerly Invitae)

Schuurs-Hoeijmakers syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014006

Submitter: Ambry Genetics

Schuurs-Hoeijmakers syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014006

Submitter: PanelApp Australia

Schuurs-Hoeijmakers syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014006

Submitter: G2P

Schuurs-Hoeijmakers syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014006

Submitter: Orphanet

Clinical Genomic Database (CGD)

Schuss-Hoeijmakers syndromeAD

Manifestation: Craniofacial; Musculoskeletal; 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: 23159249

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PACS1 variants in ClinVar

14 Conditions Cataloged

Schuurs-Hoeijmakers syndromeTotal: 756

not providedTotal: 278

Inborn genetic diseasesTotal: 159

not specifiedTotal: 114

PACS1-related disorderTotal: 52

Intellectual disabilityTotal: 8

See casesTotal: 2

Neurodevelopmental disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018026.4. 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	213 clinvar	4 clinvar	224
missense	1 clinvar	2 clinvar	317 clinvar	93 clinvar	27 clinvar	440
nonsense		1 clinvar	11 clinvar			12
start loss						0
frameshift			10 clinvar			10
splice donor/acceptor (+/-2bp)		1 clinvar	23 clinvar	1 clinvar		25
Total	1	4	368	307	31	711

Highest pathogenic variant AF is 6.197361e-7

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 19 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_018026.4	RefSeq	NP_060496.2	24	MANE Select
ENST00000320580.9	Ensembl	ENSP00000316454.4	24	MANE Select
ENST00000524784.1	Ensembl	ENSP00000435037.1	4	Standard
ENST00000524815.5	Ensembl	ENSP00000433991.1	3	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
pacs1a	Danio rerio	Structure: whole organism Quality: semi-lethal (sensu genetics) abnormal

Gene / Model

Organism

Observed Phenotype

pacs1a

Danio rerio

Structure: whole organism

Quality: semi-lethal (sensu genetics)

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Disease
Host Interactions of HIV factors
HIV Infection
Infectious disease
Nef mediated downregulation of MHC class I complex cell surface expression

Biological Process

protein localization to Golgi apparatus
regulation of defense response to virus by virus
protein localization to plasma membrane

Molecular Function

protein binding
ion channel binding

Cellular Component

Golgi apparatus
cytosol
COPI-coated vesicle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000320580
Coding exons: 24
Length: 174385
Individuals with no LoFs: 125741
Homozygous LoFs: 0
Heterozygous LoFs: 6
Defined: 125747
p: 0.0000239

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.71	302	546	0.553	0.0000315	6241
Missense (PolyPhen)		83	226.33	0.36673		2582
Synonymous	1.48	197	225	0.875	0.0000139	1919
Loss of Function	5.99	4	49.4	0.0810	0.00000237	576

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000044	0.000044	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Coat protein that is involved 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. Involved in HIV-1 nef-mediated removal of MHC-I from the cell surface to the TGN. {ECO:0000269|PubMed:11331585, ECO:0000269|PubMed:15692563}.;
Disease: DISEASE: Schuurs-Hoeijmakers syndrome (SHMS) [MIM:615009]: A syndromic form of mental retardation, a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. SHMS patients have intellectual disability in combination with distinct craniofacial features and genital abnormalities. {ECO:0000269|PubMed:23159249}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.115

Intolerance Scores

LoFtool: 0.179
RVIS EVS: -1.09
RVIS percentile EVS: 7.11

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.747

Gene Damage Prediction

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