SLC25A3

Inheritance Pattern: AR

Disease ID:MONDO:0012557

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0012557

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0012557

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0012557

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *SLC25A3* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of July 24, 2023. The *SLC25A3* gene encodes the solute carrier family 25 member 3 protein. This integral transmembrane protein acts as the major transporter of inorganic phosphate across the inner mitochondrial membrane, serving to maintain a pool of inorganic phosphate in the matrix for use in ATP synthesis. *SLC25A3* was first reported in relation to autosomal recessive primary mitochondrial disease in 2007 (PMID: 17273968), in two siblings with infantile onset hypertrophic cardiomyopathy, lactic acidosis, and hypotonia. While various names have been given to the constellation of features seen in those with *SLC25A3*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *SLC25A3* phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Evidence supporting the gene-disease relationship between *SLC25A3* and primary mitochondrial disease includes case-level data and experimental data. This curation includes four variants (two splice, one missense, one indel) in four probands across three publications (PMIDs: 17273968; 21763135; 25681081). Features seen in affected individuals include hypertrophic cardiomyopathy, developmental delay, exercise intolerance, hypotonia, and lactic acidosis. Mitochondrial respiratory chain enzyme activities in muscle were normal. Loss of function is implicated as the mechanism of disease. This gene-disease relationship is also supported by known biochemical function and a conditional knock-out mouse model of SLC25A3 (PMIDs: 24658400; 33340416). In summary, there is moderate evidence to support the relationship between *SLC25A3* and autosomal recessive primary mitochondrial disease. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on July 24, 2023 (SOP Version 9).