EHHADH

Inheritance Pattern: AD

Disease ID:MONDO:0014275

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0014275

Submitter: ClinGen

The relationship between *EHHADH* and Fanconi renotubular syndrome 3, an autosomal dominant disorder, was evaluated using the ClinGen Clinical Validity Framework as of March, 2023. *EHHADH* encodes enoyl-CoA hydratase and 3-hydroxyacyl CoA dehydrogenase, a bifunctional enzyme (a.k.a L-bifunctional protein) and is one of the four enzymes of the peroxisomal beta-oxidation pathway. A single heterozygous missense variant in this gene has been reported in the literature to cause Fanconi renotubular syndrome 3. *EHHADH* was first reported in relation to autosomal dominant Fanconi renotubular syndrome 3 in 2014. (Klootwijk et al, PMID: 24401050). To the best of our knowledge, the Glu3Lys missense variant is the only recurrent pathogenic variant identified in this gene. Summary of Case Level Data (4.1 points): The same heterozygous missense variant (Glu3Lys) has been reported in 5 probands across 5 publications (PMIDs: 24401050, 1627757, 40800210, 40242153, 41117969). An additional publication not ndexed in PubMed (Seaby et al, 2017) notes a de novo Glu3Lys variant in EHHADH identified by trio WES adding 1 pt to the case-level evidence. Functional evidence shows that this primarily peroxisomal protein is mistargeted to the mitochondria as the variant, Glu3Lys, creates a mitochondrial-targeting signal and interferes with mitochondrial function by interacting with the mitochondrial trifunctional protein (PMID: 24401050, 27160910). The mechanism for disease is expected to be dominant negative. Summary of experimental data (1 point): This gene-disease association is supported by limited experimental evidence. The *EHHADH* protein is shown to be expressed in the renal proximal tubules, which are tissues relevant to the disease (PMIDs: 24401050, 10336479). In addition, experiments with the variant expressed in proximal tubular cells show functional impairment and confirm mistargeting of the protein to the mitochondria (PMIDs: 24401050, 10336479). In summary, there is limited evidence to support the gene-disease relationship of *EHHADH* and Fanconi renotubular syndrome 3. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This gene-disease pair was originally evaluated by the Peroxisomal GCEP on Mar 3, 2023. It was reevaluated on Mar 6, 2026 (SOP v12). Although four new cases were published (PMIDs: 40800210, 40242153, 41117969, Seaby et al, 2017), the classification did not change.

Inheritance Pattern: AD

Disease ID:MONDO:0014275

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0007600

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0014275

Submitter: Ambry Genetics