TRAPPC11

protein-coding

trafficking protein particle complex subunit 11, the group of Trafficking protein particle complex subunits

Gene summary

The protein encoded by this gene is a subunit of the TRAPP (transport protein particle) tethering complex, which functions in intracellular vesicle trafficking. This subunit is involved in early stage endoplasmic reticulum-to-Golgi vesicle transport. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jan 2013]

Previous symbols:

C4orf41

MANE transcript

NM_021942.6

Inheritance

ClinVar variants

P:76U:443B:260

Top phenotype

Muscular dystrophy, limb-girdle, autosomal recessive, 18

gnomAD constraint

pLI —, LoF o/e 0.41

Max pathogenic AF

—

Genomic locus

chr4:183,659,267-183,713,594

External References & Databases

Ensembl (ENSG00000168538)

Transcript & Mutation Effects

hg38 • Region Span ~54.3 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive limb-girdle muscular dystrophy type R18STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014144

Submitter: PanelApp Australia

autosomal recessive limb-girdle muscular dystrophy type R18DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014144

Submitter: Myriad Women's Health

autosomal recessive limb-girdle muscular dystrophy type R18DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014144

Submitter: G2P

autosomal recessive limb-girdle muscular dystrophy type R18STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014144

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive limb-girdle muscular dystrophy type R18STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014144

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

autosomal recessive limb-girdle muscular dystrophyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0015152

Submitter: ClinGen

*TRAPPC11* was first reported in relation to autosomal recessive limb-girdle muscular dystrophy (LGMDR18 included) in 2013 (Bögershausen et al., PMID: 23830518). Autosomal recessive limb-girdle muscular dystrophy is typically characterized by childhood-onset of proximal muscle weakness resulting in gait abnormalities and scapular winging. Many patients have elevated serum creatine kinase. A subset of patients displayed hyperkinetic movement disorder with chorea, ataxia, or dystonia and global developmental delay. Additional phenotypes such as alacrima, achalasia, cataracts, or hepatic steatosis have been observed in the literature. *TRAPC11* has been noted to be associated with autosomal recessive limb-girdle muscular dystrophy, although many authors have noted a phenotypic expansion in the literature, where the term *TRAPPC11*-related myopathy has been coined. ORPHANET lists intellectual disability-hyperkinetic movement-truncal ataxia syndrome (ORPHA:369847) and Triple A syndrome (ORPHA:869) as additional gene-disease assertions. For the purposes of this curation, cases have been scored under the autosomal recessive limb-girdle muscular dystrophy (LGMDR18 included) disease entity, which falls under the umbrella term of *TRAPPC11*-related myopathies in MONDO. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Summary of Case Level Data: 12 POINTS. Variants in this gene have been reported in at least 14 probands in 9 publications (PMIDs: 23830518, 26322222, 27707803, 28827486, 31575891, 30105108, 29855340, 27862579, 34648194). Variants in this gene segregated with disease in 7 additional family members in 2 families (PMID:23830518). Not all probands were scored due to the absence of in trans confirmation of compound heterozygous variants, however, the maximum score for genetic evidence of 12 points has been reached. The majority of pathogenic variants in *TRAPPC11* reported in ClinVar are nonsense or frameshift variants where loss of function is the mechanism of disease. Summary of Experimental Data: 2.5 POINTS. This gene-disease association is also supported by animal model and functional alteration in human cell line (PMID: 26912795, 21525244). Loss-of-function mutations in the zebrafish ortholog of C11 have been found in the foie gras mutant, characterized by steatohepatitis and eye development defects (PMID:26912795). Mutant *TRAPPC11* zebrafish exhibits a phenotype similar to that observed in humans with respect to Golgi complex formation and endoplasmic reticulum organization supporting the role of *TRAPPC11* in the characteristic muscle phenotypes. Research conducted using HeLa cell lines revealed the role of *TRAPPC11* subunit it protein glycosylation. In HeLa cells siRNA knockdown of C11 leads to impaired binding of other TRAPP components, functional impairment of the complex, retention of secretory proteins in the ERGIC, and fragmentation of the Golgi apparatus (PMID:21525244). In summary, there is definitive evidence to support this gene-disease relationship. 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 Limb-Girdle Muscular Dystrophy GCEP on the meeting date of December 14th, 2021 (SOP Version 8).

triple-A syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009279

Submitter: Orphanet

intellectual disability-hyperkinetic movement-truncal ataxia syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018243

Submitter: Orphanet

autosomal recessive limb-girdle muscular dystrophy type R18SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014144

Submitter: Orphanet

Clinical Genomic Database (CGD)

Muscular dystrophy, limb-girdle, autosomal recessive, 18AR

Manifestation: 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: 23830518; 27707803; 28827486

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TRAPPC11 variants in ClinVar

11 Conditions Cataloged

Autosomal recessive limb-girdle muscular dystrophy type R18Total: 863

not providedTotal: 219

Inborn genetic diseasesTotal: 127

not specifiedTotal: 65

TRAPPC11-related disorderTotal: 19

Autosomal recessive limb-girdle muscular dystrophyTotal: 5

Limb-girdle muscular dystrophyTotal: 2

Muscular dystrophy, limb-girdle, autosomal recessive 23Total: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_021942.6. 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			12 clinvar	238 clinvar	1 clinvar	251
missense		5 clinvar	424 clinvar	19 clinvar	2 clinvar	450
nonsense	12 clinvar	11 clinvar	3 clinvar			26
start loss			1 clinvar			1
frameshift	18 clinvar	14 clinvar				32
splice donor/acceptor (+/-2bp)	1 clinvar	15 clinvar	3 clinvar			19
Total	31	45	443	257	3	779

Highest pathogenic variant AF is 0.00006485206

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 39 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_021942.6	RefSeq	NP_068761.4	29	MANE Select
ENST00000334690.11	Ensembl	ENSP00000335371.6	29	MANE Select
NM_199053.3	RefSeq	NP_951008.1	30	Standard
ENST00000357207.8	Ensembl	ENSP00000349738.4	30	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
trappc11	Danio rerio	Structure: hepatocyte Quality: increased size abnormal

Gene / Model

Organism

Observed Phenotype

trappc11

Danio rerio

Structure: hepatocyte

Quality: increased size

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Vesicle-mediated transport
Membrane Trafficking
Rab regulation of trafficking
RAB GEFs exchange GTP for GDP on RABs

Biological Process

endoplasmic reticulum to Golgi vesicle-mediated transport
Golgi organization
protein complex oligomerization
regulation of protein complex stability

Molecular Function

protein binding
Rab guanyl-nucleotide exchange factor activity

Cellular Component

Golgi apparatus
cytosol
TRAPP complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000334690
Coding exons: 29
Length: 54326
Individuals with no LoFs: 125670
Homozygous LoFs: 0
Heterozygous LoFs: 78
Defined: 125748
p: 0.000310

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.932	534	598	0.893	0.0000300	7426
Missense (PolyPhen)		68	92.014	0.73902		1085
Synonymous	0.533	209	219	0.954	0.0000119	2132
Loss of Function	4.46	28	67.5	0.415	0.00000349	814

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00036	0.00035	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00034	0.00033	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.00039	0.00039	rare
South Asian	0.00031	0.00029	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in endoplasmic reticulum to Golgi apparatus trafficking at a very early stage. {ECO:0000269|PubMed:21525244, ECO:0000269|PubMed:27862579}.;
Disease: DISEASE: Limb-girdle muscular dystrophy 2S (LGMD2S) [MIM:615356]: A form of limb-girdle muscular dystrophy characterized by proximal muscle weakness with childhood onset, resulting in gait abnormalities and scapular winging. Serum creatine kinase is increased. A subset of patients may show a hyperkinetic movement disorder with chorea, ataxia, or dystonia and global developmental delay. {ECO:0000269|PubMed:23830518}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.106

Intolerance Scores

RVIS EVS: -0.97
RVIS percentile EVS: 8.99

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: N
Indispensability score: 0.114

Gene Damage Prediction

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