REEP1

protein-coding

receptor accessory protein 1, the group of Receptor accessory proteins

Gene summary

This gene encodes a mitochondrial protein that functions to enhance the cell surface expression of odorant receptors. Mutations in this gene cause spastic paraplegia autosomal dominant type 31, a neurodegenerative disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

Previous symbols:

C2orf23

MANE transcript

NM_001371279.1

Inheritance

AD, AR

ClinVar variants

P:101U:145B:57

Top phenotype

Spastic paraplegia 31, autosomal dominant; Neuronopathy, distal hereditary motor, autosomal dominant 12; Neuronopathy, distal hereditary motor, autosomal recessive 6

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr2:86,213,993-86,338,083

External References & Databases

Ensembl (ENSG00000068615)

Transcript & Mutation Effects

hg38 • Region Span ~124.1 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neuronopathy, distal hereditary motor, type 5BSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013884

Submitter: Labcorp Genetics (formerly Invitae)

hereditary spastic paraplegia 31SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012453

Submitter: Orphanet

neuronopathy, distal hereditary motor, type 5BLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0013884

Submitter: Ambry Genetics

hereditary spastic paraplegia 31DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012453

Submitter: Ambry Genetics

spinal muscular atrophy, distal, autosomal recessive, 6LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0859279

Submitter: Labcorp Genetics (formerly Invitae)

spinal muscular atrophy, distal, autosomal recessive, 6STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0859279

Submitter: PanelApp Australia

hereditary spastic paraplegia 31STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012453

Submitter: PanelApp Australia

hereditary spastic paraplegia 31STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012453

Submitter: Labcorp Genetics (formerly Invitae)

neuronopathy, distal hereditary motor, type 5BSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013884

Submitter: PanelApp Australia

spinal muscular atrophy, distal, autosomal recessive, 6LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0859279

Submitter: Ambry Genetics

neuronopathy, distal hereditary motor, type 5ASUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015353

Submitter: Orphanet

Clinical Genomic Database (CGD)

Spastic paraplegia 31, autosomal dominant; Neuronopathy, distal hereditary motor, autosomal dominant 12; Neuronopathy, distal hereditary motor, autosomal recessive 6AD/AR

Manifestation: 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: 16826527; 18321925; 19034539; 22703882; 27066569; 31872057; 34193129

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to REEP1 variants in ClinVar

13 Conditions Cataloged

Hereditary spastic paraplegia 31Total: 291

not providedTotal: 101

Inborn genetic diseasesTotal: 53

REEP1-related disorderTotal: 38

not specifiedTotal: 27

Hereditary spastic paraplegiaTotal: 18

Neuronopathy, distal hereditary motor, type 5BTotal: 15

Spinal muscular atrophy, distal, autosomal recessive, 6Total: 6

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001371279.1. 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			9 clinvar	49 clinvar		58
missense	3 clinvar	14 clinvar	129 clinvar	7 clinvar	1 clinvar	154
nonsense	10 clinvar	10 clinvar				20
start loss		2 clinvar				2
frameshift	21 clinvar	14 clinvar	6 clinvar			41
splice donor/acceptor (+/-2bp)	16 clinvar	11 clinvar	1 clinvar			28
Total	50	51	145	56	1	303

Highest pathogenic variant AF is 0.000006574622

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 43 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001371279.1	RefSeq	NP_001358208.1	9	MANE Select
ENST00000538924.7	Ensembl	ENSP00000438346.3	9	MANE Select
NM_001164730.2	RefSeq	NP_001158202.1	7	Standard
NM_001164731.2	RefSeq	NP_001158203.1	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Signaling by GPCR
Signal Transduction
Olfactory Signaling Pathway
G alpha (s) signalling events
GPCR downstream signalling

Biological Process

regulation of intracellular transport
protein insertion into membrane
endoplasmic reticulum tubular network organization

Molecular Function

protein binding
microtubule binding
olfactory receptor binding

Cellular Component

cytoplasm
endoplasmic reticulum
endoplasmic reticulum membrane
membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000538924
Coding exons: 7
Length: 124091
Individuals with no LoFs: 125716
Homozygous LoFs: 0
Heterozygous LoFs: 1
Defined: 125717
p: 0.00000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.35	80	122	0.655	0.00000725	1334
Missense (PolyPhen)		15	33.103	0.45313		374
Synonymous	-0.331	52	49.0	1.06	0.00000341	406
Loss of Function	3.34	0	13.0	0.00	6.47e-7	149

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	0.0	absent
European (Non-Finnish)	0.0000088	0.0000088	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Required for endoplasmic reticulum (ER) network formation, shaping and remodeling; it links ER tubules to the cytoskeleton. May also enhance the cell surface expression of odorant receptors (PubMed:20200447). May play a role in long-term axonal maintenance (PubMed:24478229). {ECO:0000269|PubMed:20200447, ECO:0000269|PubMed:24478229}.;
Disease: DISEASE: Neuronopathy, distal hereditary motor, 5B (HMN5B) [MIM:614751]: A disorder characterized by distal muscular atrophy mainly affecting the upper extremities, in contrast to other distal motor neuronopathies. These constitute a heterogeneous group of neuromuscular diseases caused by selective degeneration of motor neurons in the anterior horn of the spinal cord, without sensory deficit in the posterior horn. The overall clinical picture consists of a classical distal muscular atrophy syndrome in the legs without clinical sensory loss. The disease starts with weakness and wasting of distal muscles of the anterior tibial and peroneal compartments of the legs. Later on, weakness and atrophy may expand to the proximal muscles of the lower limbs and/or to the distal upper limbs. HMN5B is characterized by onset in the first or second decade of distal muscle weakness and atrophy, primarily affecting the intrinsic hand muscles, but also affecting the lower legs, resulting in abnormal gait and pes cavus. {ECO:0000269|PubMed:22703882}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.112

Intolerance Scores

LoFtool: 0.107
RVIS EVS: 0.17
RVIS percentile EVS: 65.56

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.0542

Gene Damage Prediction

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