Lipodystrophy - childhood onset

Gene: EPHX1

Amber List (moderate evidence)

EPHX1 (epoxide hydrolase 1)
EnsemblGeneIds (GRCh38): ENSG00000143819
EnsemblGeneIds (GRCh37): ENSG00000143819
OMIM: 132810, Gene2Phenotype
EPHX1 is in 6 panels

1 review

Achchuthan Shanmugasundram (Genomics England Curator)

Green List (high evidence)

Comment on list classification: There is sufficient evidence available (two unrelated cases and functional studies) in support of the association of this gene with lipodystrophy and severe insulin resistance. Hence, this gene can be promoted to green rating in the next GMS review.
Created: 8 Aug 2023, 6:10 a.m. | Last Modified: 8 Aug 2023, 6:10 a.m.
Panel Version: 4.34
Two unrelated cases presenting with lipoatrophic diabetes were identified with de novo variants in EPHX1 gene (patient 1: p.Thr333Pro; patient 2: p.Gly430Arg). The disease was characterised by loss of adipose tissue, insulin resistance, and multiple organ dysfunction. Functional analysis showed that these variants protein aggregation within the endoplasmic reticulum and to a loss of its hydrolysis activity. In addition, CRISPR-Cas9-mediated EPHX1 knockout (KO) abolished adipocyte differentiation and decreased insulin response.

This gene has not yet been associated with relevant phenotypes in OMIM or in Gene2Phenotype.
Created: 8 Aug 2023, 6:04 a.m. | Last Modified: 8 Aug 2023, 6:11 a.m.
Panel Version: 4.34
This gene was added on recommendation of NHSE Genomic Medicine Service:
EPHX1 is an epoxide hydroxylase, highly expressed in liver and adipose tissue. De novo missense mutations (p.Thr333Pro and p.Gly430Arg) in EPHX1 carried in heterozygosity were implicated in a lipoatrophic diabetes syndrome in two unrelated probands (PMID: 34342583). In vitro characterisation demonstrated loss of enzyme activity in these two mutants and localisation studies demonstrated aggregation of the mutant EPHX1 isoforms in the ER, suggestive of a dominant negative mechanism of action. Consistent with a causal role for EPHX1 in the affected probands' syndrome, circulating epoxy fatty acids were found to be elevated. Variants implicated in the described clinical syndrome caused EPHX1 to form oligomeric complexes and aggregate in the ER. As such it is likely that simple loss of function mutations in EPHX1 do not cause this syndrome, and a dominant negative effect of the EPHX1 mutants is likely the causal mechanism. Consistent with this EPHX1 appears to be LOF tolerant (pLI gnomad = 0,
Created: 2 Aug 2023, 11:35 a.m. | Last Modified: 7 Aug 2023, 1:02 p.m.
Panel Version: 4.31

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Lipodystrophy, Severe Insulin Resistance


Mode of pathogenicity


Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
  • Expert Review Amber
  • Expert list
  • lipodystrophy, MONDO:0006573
  • Insulin resistance, HP:0000855
Q3_23_promote_green Q3_23_NHS_review
Clinvar variants
Variants in EPHX1
Mode of Pathogenicity
Panels with this gene

History Filter Activity

8 Aug 2023, Gel status: 2

Added Tag, Added Tag

Achchuthan Shanmugasundram (Genomics England Curator)

Tag Q3_23_promote_green tag was added to gene: EPHX1. Tag Q3_23_NHS_review tag was added to gene: EPHX1.

8 Aug 2023, Gel status: 2

Entity classified by Genomics England curator

Achchuthan Shanmugasundram (Genomics England Curator)

Gene: ephx1 has been classified as Amber List (Moderate Evidence).

8 Aug 2023, Gel status: 1

Set Phenotypes

Achchuthan Shanmugasundram (Genomics England Curator)

Phenotypes for gene: EPHX1 were changed from Lipodystrophy, Severe Insulin Resistance to lipodystrophy, MONDO:0006573; Insulin resistance, HP:0000855

8 Aug 2023, Gel status: 1

Set publications

Achchuthan Shanmugasundram (Genomics England Curator)

Publications for gene: EPHX1 were set to

2 Aug 2023, Gel status: 1

Created, Added New Source, Set mode of inheritance, Set Phenotypes, Set mode of pathogenicity

Achchuthan Shanmugasundram (Genomics England Curator)

gene: EPHX1 was added gene: EPHX1 was added to Lipodystrophy - childhood onset. Sources: Expert list,NHS GMS Mode of inheritance for gene: EPHX1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: EPHX1 were set to Lipodystrophy, Severe Insulin Resistance Mode of pathogenicity for gene: EPHX1 was set to Other