GeneBe

ELOVL4

protein-coding

ELOVL fatty acid elongase 4

Gene summary

This gene encodes a membrane-bound protein which is a member of the ELO family, proteins which participate in the biosynthesis of fatty acids. Consistent with the expression of the encoded protein in photoreceptor cells of the retina, mutations and small deletions in this gene are associated with Stargardt-like macular dystrophy (STGD3) and autosomal dominant Stargardt-like macular dystrophy (ADMD), also referred to as autosomal dominant atrophic macular degeneration. [provided by RefSeq, Jul 2008]

Previous symbols:
  • STGD2
  • STGD3
  • SCA34

MANE transcript

NM_022726.4

Inheritance

AR, AD

ClinVar variants

P:33U:139B:72

Top phenotype

Ichthyosis, spastic quadriplegia, and mental retardation; Spinocerebellar ataxia 34; Startgardt disease 3

gnomAD constraint

pLI —, LoF o/e 0.16

Max pathogenic AF

—

Genomic locus

chr6:79,914,814-79,947,553

External References & Databases

Ensembl (ENSG00000118402)NCBI Gene (6785)OMIM (605512)HGNC:14415GenCCUniProt (Q9GZR5)AlphaFoldClinVar (ELOVL4)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~32.7 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital ichthyosis-intellectual disability-spastic quadriplegia syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013760

Submitter: PanelApp Australia

Stargardt disease 3STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0010819

Submitter: Labcorp Genetics (formerly Invitae)

spinocerebellar ataxia type 34STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007574

Submitter: Labcorp Genetics (formerly Invitae)

congenital ichthyosis-intellectual disability-spastic quadriplegia syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013760

Submitter: G2P

spinocerebellar ataxia type 34MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0007574

Submitter: Ambry Genetics

spinocerebellar ataxia type 34STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007574

Submitter: PanelApp Australia

spinocerebellar ataxia type 34SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007574

Submitter: Orphanet

ELOVL4-related maculopathySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0700227

Submitter: PanelApp Australia

ELOVL4-related maculopathyDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0700227

Submitter: ClinGen

*ELOVL4* was first reported in relation to autosomal dominant Stargardt disease/macular degeneration in 2001 (PMID: 11138005). Patients presented with phenotypes consistent with dominant Stargardt disease/macular degeneration. Three variants that have been reported from three publications publications (PMIDs: 11138005, 11726641, and 15557430) are included in this curation. In 5 families from the US or Canada, Zhang et al. (PMID: 11138005) found that affected members with Stargardt-like macular dystrophy (STGD3) or autosomal dominant macular dystrophy had an identical heterozygous founder variant in the last exon of the *ELOVL4* gene, a deletion of 5 nucleotides c.790_794del, p.(Asn264Leufs*9). The other two variants, a nonsense and a frameshift, are also located in the last exon of ELOVL4. The C-terminal truncating variant in ELOVL4 has been shown to exert a dominant negative effect on wild-type ELOVL4 (PMID: 23509295, 15749821). This gene-disease association is also supported by experimental evidence that *ELOVL4* exhibits its highest expression levels in retina tissue (PMID: 15028284). Immunolocalization shows that ELOVL4 is localized to the ER of human photoreceptors (PMID: 15028284). Of note, biallelic variants in this gene have been reported in individuals with ichthyosis, spastic quadriplegia, and intellectual disability (PMID: 24571530, 33652762). This gene-disease relationship will be evaluated separately. In summary, *ELOVL4* is definitively associated with autosomal dominant inheritance of *ELOVL4*-related maculopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time without the emergence of contradictory evidence, leading to a Definitive classification according to the ClinGen template. This classification was approved by the ClinGen Retina GCEP on February 2, 2023.

spinocerebellar ataxia type 34STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007574

Submitter: Genomics England PanelApp

congenital ichthyosis-intellectual disability-spastic quadriplegia syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013760

Submitter: Labcorp Genetics (formerly Invitae)

Stargardt diseaseSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019353

Submitter: Orphanet

Stargardt disease 3DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0010819

Submitter: G2P

congenital ichthyosis-intellectual disability-spastic quadriplegia syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013760

Submitter: Orphanet

Clinical Genomic Database (CGD)

Ichthyosis, spastic quadriplegia, and mental retardation; Spinocerebellar ataxia 34; Startgardt disease 3AD/AR

Manifestation: Biochemical; Dermatologic; Neurologic; 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: 10634627; 11726641; 11138005; 15557430; 22100072; 24566826Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ELOVL4 variants in ClinVar

11 Conditions Cataloged
not providedTotal: 261
Inborn genetic diseasesTotal: 26
Stargardt disease 3Total: 19
Spinocerebellar ataxia type 34Total: 12
Congenital ichthyosis-intellectual disability-spastic quadriplegia syndromeTotal: 12
not specifiedTotal: 8
ELOVL4-related disorderTotal: 7
Retinal dystrophyTotal: 6

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_022726.4. 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
2
clinvar
66
clinvar
 68
missense
3
clinvar
5
clinvar
132
clinvar
6
clinvar
 146
nonsense
2
clinvar
4
clinvar
2
clinvar
 8
start loss
1
clinvar
 1
frameshift
12
clinvar
2
clinvar
1
clinvar
 15
splice donor/acceptor (+/-2bp)
5
clinvar
1
clinvar
 6
Total1716139720244

Highest pathogenic variant AF is 0.000011772535

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 6 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_022726.4RefSeqNP_073563.16MANE Select
ENST00000369816.5EnsemblENSP00000358831.46MANE Select
ENST00001079965.1EnsemblENSP00000749771.14Standard
ENST00001079966.1EnsemblENSP00000749772.16Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Fatty acid elongation - Homo sapiens (human)
  • Alpha Linolenic Acid and Linoleic Acid Metabolism
  • Ectoderm Differentiation
  • Metabolism of lipids
  • Fatty acyl-CoA biosynthesis

Biological Process

  • fatty acid biosynthetic process
  • unsaturated fatty acid biosynthetic process
  • detection of visible light
  • fatty acid elongation, saturated fatty acid
  • sphingolipid biosynthetic process

Molecular Function

  • protein binding
  • G protein-coupled photoreceptor activity
  • fatty acid elongase activity
  • 3-oxo-arachidoyl-CoA synthase activity
  • 3-oxo-cerotoyl-CoA synthase activity

Cellular Component

  • endoplasmic reticulum
  • integral component of endoplasmic reticulum membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000369816
Coding exons
6
Length
32769
Individuals with no LoFs
125736
Homozygous LoFs
0
Heterozygous LoFs
12
Defined
125748
p
0.0000477
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.191261690.7440.000008192068
Missense (PolyPhen)2960.2490.48134735
Synonymous-0.2846057.31.050.00000265566
Loss of Function3.41319.10.1579.98e-7198

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian0.0000540.000054rare
Finnish0.0000470.000046rare
European (Non-Finnish)0.0000700.000070rare
South Asian0.0000330.000033rare
Other0.000160.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Catalyzes the first and rate-limiting reaction of the four that constitute the long-chain fatty acids elongation cycle. This endoplasmic reticulum-bound enzymatic process, allows the addition of 2 carbons to the chain of long- and very long-chain fatty acids/VLCFAs per cycle. Condensing enzyme that specifically elongates C24:0 and C26:0 acyl-CoAs. May participate in the production of saturated and monounsaturated VLCFAs of different chain lengths that are involved in multiple biological processes as precursors of membrane lipids and lipid mediators. May play a critical role in early brain and skin development. {ECO:0000255|HAMAP-Rule:MF_03204, ECO:0000269|PubMed:20937905}.;
Disease
DISEASE: Stargardt disease 3 (STGD3) [MIM:600110]: A common hereditary macular degeneration. It is characterized by decreased central vision, atrophy of the macula and underlying retinal pigment epithelium, and frequent presence of prominent flecks in the posterior pole of the retina. {ECO:0000269|PubMed:11138005, ECO:0000269|PubMed:11581213}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Ichthyosis, spastic quadriplegia, and mental retardation (ISQMR) [MIM:614457]: A severe autosomal recessive disorder characterized by ichthyosis apparent from birth, profound psychomotor retardation with essentially no development, spastic quadriplegia, and seizures. {ECO:0000269|PubMed:22100072}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Spinocerebellar ataxia 34 (SCA34) [MIM:133190]: A form of spinocerebellar ataxia, a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCA34 is an autosomal dominant form characterized by the association of progressive cerebellar ataxia with erythrokeratodermia variabilis. {ECO:0000269|PubMed:24566826}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.0997

Intolerance Scores

LoFtool
0.545
RVIS EVS
0.39
RVIS percentile EVS
76.05

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.144

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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