SLC25A22

protein-coding

solute carrier family 25 member 22, the group of Solute carrier family 25

Gene summary

This gene encodes a mitochondrial glutamate carrier. Mutations in this gene are associated with early infantile epileptic encephalopathy. Multiple alternatively spliced variants, encoding the same protein, have been identified.[provided by RefSeq, Jul 2010]

MANE transcript

NM_001191061.2

Inheritance

AD, AR

ClinVar variants

P:25U:201B:155

Top phenotype

Epileptic encephalopathy, early infantile, 3

gnomAD constraint

pLI —, LoF o/e 0.41

Max pathogenic AF

—

Genomic locus

chr11:790,475-798,281

External References & Databases

Ensembl (ENSG00000177542)

Transcript & Mutation Effects

hg38 • Region Span ~7.8 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

genetic developmental and epileptic encephalopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100062

Submitter: Orphanet

developmental and epileptic encephalopathy, 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012245

Submitter: G2P

malignant migrating partial seizures of infancySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017385

Submitter: Orphanet

developmental and epileptic encephalopathy, 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012245

Submitter: PanelApp Australia

genetic developmental and epileptic encephalopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100062

Submitter: ClinGen

SLC22A25 was first reported in relation to autosomal recessive epileptic encephalopathy in 2005 (Molinari F, et al., 2005, PMID: 15592994) . At least 14 unique variants (e.g. missense and frameshift) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Summary of Case Level Data: 8 POINTS Variants in this gene have been reported in at least 17 probands in over 11 publications (PMIDs: 31285529, 19780765, 28255779, 25033742, 24596948, 15592994, 28454995, 31054490). Variants in this gene segregated with disease in at least 7 additional family members. The mechanism for disease is homozygous or compound heterozygous loss of function variants (PMID: 31285529). This gene-disease association is supported by animal models, expression studies, and in vitro functional assays. In summary, SLC22A25 is definitively associated with autosomal recessive epileptic encephalopathy This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

developmental and epileptic encephalopathy, 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012245

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Epileptic encephalopathy, early infantile, 3AR

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

Comments: As with other conditions involving seizures, optimal seizure control is beneficial, and awareness of genetic causes may help with medication selection

Refs: 15592994; 19780765; 24596948

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SLC25A22 variants in ClinVar

13 Conditions Cataloged

Early-infantile DEETotal: 354

not providedTotal: 152

Inborn genetic diseasesTotal: 103

not specifiedTotal: 81

Developmental and epileptic encephalopathyTotal: 80

Early Myoclonic EncephalopathyTotal: 59

Developmental and epileptic encephalopathy, 3Total: 35

SLC25A22-related disorderTotal: 13

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001191061.2. 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			4 clinvar	143 clinvar	5 clinvar	152
missense	3 clinvar	2 clinvar	187 clinvar	6 clinvar	1 clinvar	199
nonsense	6 clinvar	2 clinvar	4 clinvar			12
start loss						0
frameshift	4 clinvar	1 clinvar	2 clinvar			7
splice donor/acceptor (+/-2bp)	2 clinvar	5 clinvar	4 clinvar			11
Total	15	10	201	149	6	381

Highest pathogenic variant AF is 0.000006160628

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 101 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001191061.2	RefSeq	NP_001177990.1	9	MANE Select
ENST00000628067.3	Ensembl	ENSP00000486058.1	9	MANE Select
NM_001191060.2	RefSeq	NP_001177989.1	9	Standard
NM_001425334.1	RefSeq	NP_001412263.1	9	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Glucose-Alanine Cycle
miR-targeted genes in epithelium - TarBase
miR-targeted genes in lymphocytes - TarBase
visual signal transduction
Organic anion transporters

Biological Process

ion transport
aspartate transmembrane transport
L-glutamate transmembrane transport
malate-aspartate shuttle
L-aspartate transmembrane transport

Molecular Function

amino acid:proton symporter activity
L-glutamate transmembrane transporter activity
L-aspartate transmembrane transporter activity

Cellular Component

mitochondrial inner membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000320230
Coding exons: 9
Length: 7842
Individuals with no LoFs: 125616
Homozygous LoFs: 0
Heterozygous LoFs: 13
Defined: 125629
p: 0.0000517

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.913	168	205	0.820	0.0000153	2009
Missense (PolyPhen)		78	100.05	0.7796		984
Synonymous	-2.20	122	94.7	1.29	0.00000812	683
Loss of Function	2.09	6	14.6	0.410	6.46e-7	171

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00013	0.00012	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000055	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000038	0.000035	rare
South Asian	0.000069	0.000065	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in the transport of glutamate across the inner mitochondrial membrane. Glutamate is cotransported with H(+). {ECO:0000269|PubMed:11897791}.;

Recessive Scores

pRec: 0.122

Intolerance Scores

LoFtool: 0.354
RVIS EVS: 0.13
RVIS percentile EVS: 63.2

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.610

Gene Damage Prediction

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