SLC25A12

protein-coding

solute carrier family 25 member 12, the group of Solute carrier family 25|EF-hand domain containing

Gene summary

This gene encodes a calcium-binding mitochondrial carrier protein. The encoded protein localizes to the mitochondria and is involved in the exchange of aspartate for glutamate across the inner mitochondrial membrane. Polymorphisms in this gene may be associated with autism, and mutations in this gene may also be a cause of global cerebral hypomyelination. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Apr 2012]

MANE transcript

NM_003705.5

Inheritance

ClinVar variants

P:24U:219B:142

Top phenotype

Developmental and epileptic encephalopathy 39 with leukodystrophy

gnomAD constraint

pLI —, LoF o/e 0.24

Max pathogenic AF

—

Genomic locus

chr2:171,783,405-171,999,859

External References & Databases

Ensembl (ENSG00000115840)

Transcript & Mutation Effects

hg38 • Region Span ~216.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

developmental and epileptic encephalopathy, 39MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013056

Submitter: Ambry Genetics

developmental and epileptic encephalopathy, 39STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013056

Submitter: PanelApp Australia

developmental and epileptic encephalopathy, 39STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013056

Submitter: Labcorp Genetics (formerly Invitae)

mitochondrial diseaseMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *SLC25A12* (also referred to as *AGC1* and *Aralar*) and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of August 21, 2023. *SLC25A12* encodes the muscle and brain specific isoform of mitochondrial aspartate-glutamate carrier (Ca2+ binding), which is the regulatory component of the NADH malate-aspartate shuttle (MAS) that transfers cytosolic redox power to mitochondria. *SLC25A12* was first reported in relation to autosomal recessive primary mitochondrial disease in 2009 (PMID: 19641205), in a patient with epilepsy, spasticity, and developmental delay. While various names have been given to the constellation of features seen in those with *SLC25A12*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *SLC25A12* phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included five unique variants (three missense, one nonsense, one intronic 2bp deletion predicted to impact splicing) in four probands from three publications (PMIDs: 24515575, 31403263, 32700846). Features seen in affected individuals include epilepsy, spasticity, developmental delay, developmental regression, and optic neuropathy. Brain MRI findings include bilateral basal ganglia lesions, thin corpus callosum, hypomyelination, and cerebellar atrophy. Notably, muscle respiratory chain enzyme assays may not show deficiency in affected individuals, but ATP production, particularly in the presence of glutamate and malate, and decreased NAA on brain magnetic resonance spectroscopy (MRS) are common in affected individuals. This gene-disease association is also supported by experimental evidence given the association of *SLC25A12* with *GOT2* and *MDH2*, which both act in the mitochondrial malate aspartate shuttle and are associated with similar phenotypes (PMID: 35008954), expression in relevant brain and muscle tissue (PMID: 9722566), and *SLC25A12* knockout studies performed in mice (PMID: 15987682). Of note, a canine model of inflammatory myopathy was reviewed (PMID: 31594244) and excluded from scoring given there are no case reports of an inflammatory myopathy in humans to date. In summary, there is moderate evidence to support the relationship between *SLC25A12* and 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 August 21, 2023 (SOP Version 9).

developmental and epileptic encephalopathy, 39SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013056

Submitter: Orphanet

Clinical Genomic Database (CGD)

Developmental and epileptic encephalopathy 39 with leukodystrophyAR

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: 19641205

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SLC25A12 variants in ClinVar

6 Conditions Cataloged

not providedTotal: 498

Inborn genetic diseasesTotal: 62

Developmental and epileptic encephalopathy, 39Total: 30

SLC25A12-related disorderTotal: 11

not specifiedTotal: 6

Developmental and epileptic encephalopathy, 1Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003705.5. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			5 clinvar	134 clinvar	2 clinvar	141
missense	2 clinvar	4 clinvar	209 clinvar	4 clinvar	1 clinvar	220
nonsense	3 clinvar	2 clinvar	1 clinvar			6
start loss						0
frameshift	4 clinvar	2 clinvar	1 clinvar	1 clinvar		8
splice donor/acceptor (+/-2bp)	2 clinvar	5 clinvar	3 clinvar			10
Total	11	13	219	139	3	385

Highest pathogenic variant AF is 0.0000065763516

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 51 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003705.5	RefSeq	NP_003696.2	18	MANE Select
ENST00000422440.7	Ensembl	ENSP00000388658.2	18	MANE Select
ENST00000263812.8	Ensembl	ENSP00000263812.4	4	Standard
ENST00000426896.5	Ensembl	ENSP00000413968.1	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Argininemia
Citrullinemia Type I
Carbamoyl Phosphate Synthetase Deficiency
Argininosuccinic Aciduria
Malate-Aspartate Shuttle

Biological Process

gluconeogenesis
glutamate biosynthetic process
positive regulation of glucose metabolic process
aspartate transmembrane transport
L-glutamate transmembrane transport

Molecular Function

L-glutamate transmembrane transporter activity
calcium ion binding
acidic amino acid transmembrane transporter activity
L-aspartate transmembrane transporter activity
identical protein binding

Cellular Component

mitochondrion
mitochondrial inner membrane
integral component of membrane
myelin sheath

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000422440
Coding exons: 18
Length: 223887
Individuals with no LoFs: 125736
Homozygous LoFs: 0
Heterozygous LoFs: 12
Defined: 125748
p: 0.0000477

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.71	226	373	0.605	0.0000209	4399
Missense (PolyPhen)		49	126.07	0.38868		1508
Synonymous	-0.718	141	131	1.08	0.00000711	1360
Loss of Function	4.34	9	37.8	0.238	0.00000212	446

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000062	0.000062	rare
South Asian	0.000065	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Mitochondrial and calcium-binding carrier that catalyzes the calcium-dependent exchange of cytoplasmic glutamate with mitochondrial aspartate across the mitochondrial inner membrane (PubMed:11566871, PubMed:25410934). May have a function in the urea cycle (PubMed:11566871). {ECO:0000269|PubMed:11566871, ECO:0000269|PubMed:25410934}.;
Disease: DISEASE: Epileptic encephalopathy, early infantile, 39 (EIEE39) [MIM:612949]: A form of epileptic encephalopathy, a heterogeneous group of severe childhood onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. EIEE39 is characterized by global hypomyelination of the central nervous system, with the gray matter appearing relatively unaffected. Inheritance is autosomal recessive. {ECO:0000269|PubMed:19641205, ECO:0000269|PubMed:24515575}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.154

Intolerance Scores

LoFtool: 0.211
RVIS EVS: -0.42
RVIS percentile EVS: 25.56

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.828

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium