GeneBe

FRRS1L

protein-coding

ferric chelate reductase 1 like

Gene summary

This gene encodes a component of the outer-core of an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor protein in the brain. The encoded protein is thought to interact with inner-core components of the receptor, and play a role in the modulation of glutamate signaling. Mutations in this gene are associated with early infantile epileptic encephalopathy 37. [provided by RefSeq, Jul 2016]

Previous symbols:
  • C9orf4

MANE transcript

NM_014334.4

Inheritance

AR

ClinVar variants

P:31U:178B:85

Top phenotype

Developmental and epileptic encephalopathy 37

gnomAD constraint

pLI —, LoF o/e 0.55

Max pathogenic AF

—

Genomic locus

chr9:109,130,293-109,167,249

External References & Databases

Ensembl (ENSG00000260230)NCBI Gene (23732)OMIM (604574)HGNC:1362GenCCUniProt (Q9P0K9)AlphaFoldClinVar (FRRS1L)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~37.0 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

developmental and epileptic encephalopathy, 37STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014859

Submitter: PanelApp Australia

developmental and epileptic encephalopathy, 37STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014859

Submitter: G2P

genetic developmental and epileptic encephalopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100062

Submitter: ClinGen

FRRS1L was first reported in relation to autosomal recessive developmental and epileptic encephalopathy (DEE) in 2016 by two groups (Madeo et al., PMID: 27236917; Shaheen et al. PMID: 27239025). Typical phenotypes of individuals affected with FRRS1L-related DEE include severe intractable seizures, global developmental delay, regression, hypotonia, and movement disorders such as choreoathetosis. Eleven homozygous variants (missense and truncations) reported in 11 probands in eight publications are included in this curation (PMIDs: 27236917, 27239025, 28675162, 30525197, 31130284, 33584793, 35815844, 36703223). While a founder variant from Saudi Arabia, NM_014334.4 c.808C>T p.Gln270* (CA10575812), was found in the homozygous state in affected individuals from at least four families in three publications (PMID: 27239025, 27236917, 31054490), only one of the probands was included in the scoring as the level of relatedness between these two families is unclear (PMID: 27239025). Other variants segregated with disease in two different families resulting in a total LOD score of 5.86. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by a knockout mouse model that showed spontaneous seizures (PMID: 30692144). In summary, there is definitive evidence supporting the relationship between FRRS1L and autosomal recessive DEE. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification has been approved by ClinGen Epilepsy GCEP on the meeting date, September 17, 2024 (SOP version 11).

developmental and epileptic encephalopathy, 37MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014859

Submitter: Ambry Genetics

developmental and epileptic encephalopathy, 37STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014859

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive non-syndromic intellectual disabilitySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019502

Submitter: Orphanet

Clinical Genomic Database (CGD)

Developmental and epileptic encephalopathy 37AR

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: 27236917; 27239025Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FRRS1L variants in ClinVar

10 Conditions Cataloged
Developmental and epileptic encephalopathy, 37Total: 299
not providedTotal: 61
Inborn genetic diseasesTotal: 55
not specifiedTotal: 13
FRRS1L-related disorderTotal: 5
ChoreaTotal: 4
SeizureTotal: 4
Progressive encephalopathyTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014334.4. 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
1
clinvar
80
clinvar
 81
missense
3
clinvar
175
clinvar
5
clinvar
 183
nonsense
7
clinvar
3
clinvar
2
clinvar
 12
start loss
0
frameshift
10
clinvar
5
clinvar
 15
splice donor/acceptor (+/-2bp)
3
clinvar
 3
Total1714178850294

Highest pathogenic variant AF is 0.000071364004

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 5 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_014334.4RefSeqNP_055149.35MANE Select
ENST00000561981.5EnsemblENSP00000477141.25MANE Select
ENST00000642299.1EnsemblENSP00000495137.12Standard
ENST00000644736.1EnsemblENSP00000494579.11Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

  • regulation of postsynaptic membrane neurotransmitter receptor levels
  • regulation of glutamate receptor signaling pathway

Molecular Function

  • molecular_function

Cellular Component

  • cellular_component
  • plasma membrane
  • integral component of membrane
  • cell junction
  • synapse

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000561981
Coding exons
5
Length
36999
Individuals with no LoFs
125735
Homozygous LoFs
0
Heterozygous LoFs
10
Defined
125745
p
0.0000398
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.5811211400.8620.000007482147
Missense (PolyPhen)2637.1720.69944407
Synonymous-0.02835150.71.000.00000269734
Loss of Function1.37610.90.5515.20e-7158

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0000620.000062rare
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian0.0000590.000054rare
Finnish00.0absent
European (Non-Finnish)0.0000620.000062rare
South Asian00.0absent
Other0.000160.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Important modulator of glutamate signaling pathway. {ECO:0000269|PubMed:27236917}.;

Recessive Scores

pRec
0.120

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Indispensability pred.
N
Indispensability score
0.114

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
Feedback | API | MCP | Annotate VCF | Sitemap | About | Privacy & Terms
For research and educational, non-commercial use only. Not for clinical or diagnostic use. GeneBe does not provide medical advice. Data use for AI modeling is prohibited: if used, the cost is $0.001 per byte of downloaded uncompressed data.