RIMS1

protein-coding

regulating synaptic membrane exocytosis 1, the group of PDZ domain containing|Regulating synaptic membrane exocytosis family

Gene summary

The protein encoded by this gene is a RAS gene superfamily member that regulates synaptic vesicle exocytosis. This gene also plays a role in the regulation of voltage-gated calcium channels during neurotransmitter and insulin release. Mutations have suggested a role cognition and have been identified as the cause of cone-rod dystrophy type 7. Multiple transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Mar 2012]

Previous symbols:

RAB3IP2
CORD7

MANE transcript

NM_014989.7

Inheritance

ClinVar variants

P:3U:769B:371

Top phenotype

Cone-rod dystrophy 7

gnomAD constraint

pLI —, LoF o/e 0.19

Max pathogenic AF

—

Genomic locus

chr6:71,886,550-72,403,150

External References & Databases

Ensembl (ENSG00000079841)

Transcript & Mutation Effects

hg38 • Region Span ~516.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cone-rod dystrophy 7NO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0011355

Submitter: Illumina

autism spectrum disorderLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0005258

Submitter: Illumina

The RIMS1 gene is located on chromosome 6 at 6q13 and encodes regulating synaptic membrane exocytosis 1. This protein is a member of the RAS gene superfamily and acts to regulate synaptic vesicle exocytosis, including neurotransmitter release at the active zone. It is highly expressed in the brain, where it also regulates synaptic plasticity. RIMS1 was first reported in association with autism spectrum disorder (autosomal dominant ) in 2012 (22542183, Iossifov et al.). Evidence supporting this gene-disease relationship includes case-level data and experimental data. At least six unique variants (three frameshift, one missense, two stop-gained) have been reported in six unrelated individuals from three publications (22542183: Iossifov et al. 2012; 25284784: Dong et al. 2014; 30564305: Guo et al. 2018); three of these variants occurred de novo. Additional variants have been reported, including those inherited from an unaffected parent, but these did not meet scoring criteria. In addition to expression and biochemical function evidence (29891949: Wang et al. 2018; 22031440: Kang et al. 2011), this gene-disease relationship is also supported by animal model data, in that RIMS1alpha knockout mice display deficits in learning and memory (15066271: Powell et al. 2004). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. MIM603649:Cone-rod dystrophy 7 Of note, this gene-disease association has also been implicated in cone-rod dystrophy. This association will be assessed separately.

cone-rod dystrophy 7STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011355

Submitter: Labcorp Genetics (formerly Invitae)

cone-rod dystrophySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015993

Submitter: Orphanet

cone-rod dystrophy 7LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0011355

Submitter: G2P

cone-rod dystrophyLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0015993

Submitter: PanelApp Australia

cone-rod dystrophy 7LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0011355

Submitter: Ambry Genetics

autismSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0005260

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Cone-rod dystrophy 7AD

Manifestation: Ophthalmologic

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: 9634506; 12659814

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RIMS1 variants in ClinVar

10 Conditions Cataloged

not providedTotal: 1268

not specifiedTotal: 407

Cone-rod dystrophy 7Total: 94

RIMS1-related disorderTotal: 32

Retinal dystrophyTotal: 16

Retinitis pigmentosaTotal: 2

Leber congenital amaurosisTotal: 1

Autism spectrum disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014989.7. 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			13 clinvar	312 clinvar	6 clinvar	331
missense		1 clinvar	731 clinvar	50 clinvar	2 clinvar	784
nonsense			14 clinvar			14
start loss						0
frameshift			2 clinvar	1 clinvar		3
splice donor/acceptor (+/-2bp)		2 clinvar	9 clinvar			11
Total	0	3	769	363	8	1143

Highest pathogenic variant AF is 0.0001345483

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 118 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014989.7	RefSeq	NP_055804.2	34	MANE Select
ENST00000521978.6	Ensembl	ENSP00000428417.1	34	MANE Select
NM_001168407.2	RefSeq	NP_001161879.1	25	Standard
NM_001168408.2	RefSeq	NP_001161880.1	21	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Synaptic vesicle cycle - Homo sapiens (human)
Retrograde endocannabinoid signaling - Homo sapiens (human)
Synaptic Vesicle Pathway
Effects of Botulinum toxin
Neuronal System

Biological Process

intracellular protein transport
visual perception
positive regulation of gene expression
synaptic vesicle exocytosis
calcium ion regulated exocytosis

Molecular Function

RNA binding
protein binding
Rab GTPase binding
GTPase regulator activity
ion channel binding

Cellular Component

cytosol
plasma membrane
cell junction
presynaptic membrane
synapse

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000521978
Coding exons: 34
Length: 516440
Individuals with no LoFs: 124571
Homozygous LoFs: 1
Heterozygous LoFs: 70
Defined: 124642
p: 0.000285

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.01	767	940	0.816	0.0000511	10851
Missense (PolyPhen)		300	426.98	0.70261		4990
Synonymous	0.293	337	344	0.980	0.0000184	3327
Loss of Function	7.38	19	97.7	0.195	0.00000620	1063

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00019	0.00019	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00028	0.00028	rare
Finnish	0.00079	0.00079	rare
European (Non-Finnish)	0.00032	0.00032	rare
South Asian	0.00027	0.00023	rare
Other	0.00017	0.00017	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Rab effector involved in exocytosis (By similarity). May act as scaffold protein that regulates neurotransmitter release at the active zone. Essential for maintaining normal probability of neurotransmitter release and for regulating release during short- term synaptic plasticity (By similarity). Plays a role in dendrite formation by melanocytes (PubMed:23999003). {ECO:0000250|UniProtKB:Q99NE5, ECO:0000269|PubMed:23999003}.;
Disease: DISEASE: Cone-rod dystrophy 7 (CORD7) [MIM:603649]: An inherited retinal dystrophy characterized by retinal pigment deposits visible on fundus examination, predominantly in the macular region, and initial loss of cone photoreceptors followed by rod degeneration. This leads to decreased visual acuity and sensitivity in the central visual field, followed by loss of peripheral vision. Severe loss of vision occurs earlier than in retinitis pigmentosa, due to cone photoreceptors degenerating at a higher rate than rod photoreceptors. {ECO:0000269|PubMed:12659814}. Note=The disease may be caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.151

Intolerance Scores

LoFtool: 0.819
RVIS EVS: -1.54
RVIS percentile EVS: 3.32

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.741

Gene Damage Prediction

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