GeneBe

SCARB2

protein-coding

scavenger receptor class B member 2, the group of Scavenger receptors

Gene summary

The protein encoded by this gene is a type III glycoprotein that is located primarily in limiting membranes of lysosomes and endosomes. Earlier studies in mice and rat suggested that this protein may participate in membrane transportation and the reorganization of endosomal/lysosomal compartment. The protein deficiency in mice was reported to impair cell membrane transport processes and cause pelvic junction obstruction, deafness, and peripheral neuropathy. Further studies in human showed that this protein is a ubiquitously expressed protein and that it is involved in the pathogenesis of HFMD (hand, foot, and mouth disease) caused by enterovirus-71 and possibly by coxsackievirus A16. Mutations in this gene caused an autosomal recessive progressive myoclonic epilepsy-4 (EPM4), also known as action myoclonus-renal failure syndrome (AMRF). Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Feb 2011]

Previous symbols:
  • CD36L2

MANE transcript

NM_005506.4

Inheritance

AR

ClinVar variants

P:42U:220B:120

Top phenotype

Epilepsy, progressive myoclonic 4, with or without renal failure

gnomAD constraint

pLI —, LoF o/e 0.44

Max pathogenic AF

—

Genomic locus

chr4:76,158,737-76,234,536

External References & Databases

Ensembl (ENSG00000138760)NCBI Gene (950)OMIM (602257)HGNC:1665GenCCUniProt (Q14108)AlphaFoldClinVar (SCARB2)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~75.8 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

progressive myoclonus epilepsySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0020074

Submitter: PanelApp Australia

action myoclonus-renal failure syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009699

Submitter: Orphanet

progressive myoclonus epilepsyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0020074

Submitter: ClinGen

SCARB2 was first reported in relation to autosomal recessive Progressive Myoclonic Epilepsy (PME) in 2008 (Berkovic et al., PMID: 18308289). At least 25 variants have been reported in humans. Renal dysfunction has been reported in about 50% of patients with SCARB2-related conditions, and therefore may represent phenotypic variability associated with PME (Tian et al. 2018, PMID: 29605618). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 6 unrelated probands in 3 publications (Berkovic et al. 2008, PMID: 18308289; Balreira et al. 2008, PMID: 18424452; Fu et al. 2014, PMID: 23659519). More evidence is available in the literature, but the maximum score for genetic evidence has been reached. The mechanism for disease is homozygous loss of function (Blanz et al. 2010, PMID: 19933215). This gene-disease association is supported by in vitro functional assays using patient cells (Blanz et al. 2010, PMID: 19933215). In summary, SCARB2 is definitively associated with autosomal recessive Progressive Myoclonic Epilepsy. 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 EIEE Working Group on 8/18/20 (SOP Version 7).

action myoclonus-renal failure syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009699

Submitter: Natera

action myoclonus-renal failure syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009699

Submitter: Ambry Genetics

Unverricht-Lundborg syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009698

Submitter: Orphanet

action myoclonus-renal failure syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009699

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Epilepsy, progressive myoclonic 4, with or without renal failureAR

Manifestation: Neurologic; Renal

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

Comments: In addition to other manifestations, renal dysfunction and cardiomyopathy have been reported; Renal transplant has been described

Refs: 15364701; 17030781; 18424452; 18308289; 19847901; 21782476; 21670406; 22032306; 22050460; 22767442Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SCARB2 variants in ClinVar

8 Conditions Cataloged
Progressive myoclonic epilepsyTotal: 384
Action myoclonus-renal failure syndromeTotal: 123
not providedTotal: 111
Inborn genetic diseasesTotal: 95
not specifiedTotal: 46
SCARB2-related disorderTotal: 25
Focal segmental glomerulosclerosisTotal: 3
Self-limited epilepsy with centrotemporal spikesTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005506.4. 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.

EffectPLPVUSLBBSum
synonymous
4
clinvar
107
clinvar
1
clinvar
 112
missense
204
clinvar
11
clinvar
1
clinvar
 216
nonsense
5
clinvar
4
clinvar
1
clinvar
 10
start loss
0
frameshift
13
clinvar
7
clinvar
6
clinvar
 26
splice donor/acceptor (+/-2bp)
4
clinvar
9
clinvar
5
clinvar
 18
Total22202201182382

Highest pathogenic variant AF is 0.00015123904

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 41 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_005506.4RefSeqNP_005497.112MANE Select
ENST00000264896.8EnsemblENSP00000264896.212MANE Select
NM_001204255.2RefSeqNP_001191184.19Standard
ENST00000452464.6EnsemblENSP00000399154.29Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
scarb2aDanio rerio

Structure: melanocyte

Quality: quality

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Lysosome - Homo sapiens (human)
  • Primary Focal Segmental Glomerulosclerosis FSGS
  • Vesicle-mediated transport
  • Membrane Trafficking
  • Clathrin-mediated endocytosis

Biological Process

  • protein targeting to lysosome
  • receptor-mediated endocytosis
  • positive regulation of neuron projection development
  • aminophospholipid transport
  • regulation of cellular carbohydrate catabolic process

Molecular Function

  • virus receptor activity
  • phosphatidylserine binding
  • transmembrane signaling receptor activity
  • scavenger receptor activity
  • protein binding

Cellular Component

  • Golgi membrane
  • lysosomal membrane
  • endoplasmic reticulum membrane
  • plasma membrane
  • focal adhesion

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000264896
Coding exons
12
Length
55157
Individuals with no LoFs
125699
Homozygous LoFs
0
Heterozygous LoFs
49
Defined
125748
p
0.000195
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.321942530.7660.00001253158
Missense (PolyPhen)5076.2980.65533943
Synonymous0.9238596.50.8810.00000514901
Loss of Function2.611125.10.4380.00000124301

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0000620.000062rare
Latino/Admixed American0.000200.00020rare
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish0.0000460.000046rare
European (Non-Finnish)0.000310.00031rare
South Asian0.000160.00016rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Acts as a lysosomal receptor for glucosylceramidase (GBA) targeting. {ECO:0000269|PubMed:18022370}.;
Disease
DISEASE: Epilepsy, progressive myoclonic 4, with or without renal failure (EPM4) [MIM:254900]: An autosomal recessive progressive myoclonic epilepsy associated with renal failure in some cases. Cognitive function is preserved. Myoclonus is a brief, involuntary twitching of a muscle or a group of muscles. {ECO:0000269|PubMed:18308289, ECO:0000269|PubMed:18424452, ECO:0000269|PubMed:19454373, ECO:0000269|PubMed:21670406}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Genetic variants in SCARB2 can act as modifier of the phenotypic expression and severity of Gaucher disease. {ECO:0000269|PubMed:21796727}.;

Recessive Scores

pRec
0.447

Intolerance Scores

LoFtool
0.540
RVIS EVS
0.49
RVIS percentile EVS
79.38

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.533

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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