SUCLG1

protein-coding

succinate-CoA ligase GDP/ADP-forming subunit alpha

Gene summary

This gene encodes the alpha subunit of the heterodimeric enzyme succinate coenzyme A ligase. This enzyme is targeted to the mitochondria and catalyzes the conversion of succinyl CoA and ADP or GDP to succinate and ATP or GTP. Mutations in this gene are the cause of the metabolic disorder fatal infantile lactic acidosis and mitochondrial DNA depletion. [provided by RefSeq, Feb 2010]

MANE transcript

NM_003849.4

Inheritance

ClinVar variants

P:38U:138B:82

Top phenotype

Mitochondrial DNA depletion syndrome 9 (encephalomyopathic type with methylmalonic aciduria)

gnomAD constraint

pLI —, LoF o/e 0.49

Max pathogenic AF

—

Genomic locus

chr2:84,423,528-84,460,045

External References & Databases

Ensembl (ENSG00000163541)

Transcript & Mutation Effects

hg38 • Region Span ~36.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mitochondrial DNA depletion syndrome 9DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009504

Submitter: G2P

mitochondrial DNA depletion syndrome 9STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009504

Submitter: PanelApp Australia

Leigh syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between SUCLG1 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of March 25, 2019. 18 articles were reviewed. Variants in SUCLG1 were first reported in relation to autosomal recessive Leigh syndrome spectrum in 2010 (PMID 19526370). At least 16 unique variants predicted to cause a loss of or reduced function of the protein have been reported in ClinVar, suggesting homozygous loss of function is the mechanism of disease for this gene. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 6 probands with Leigh syndrome spectrum in 5 publications (PMID19526370, 20197121, 20693550, 20453710, 29217198). This gene-disease association is further supported by the function of the gene product, protein interaction, expression, and alterations in patient cell lines. In summary, there is moderate evidence to support the relationship between SUCLG1 and autosomal recessive Leigh syndrome spectrum. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on March 25, 2019 (SOP Version 6).

mitochondrial DNA depletion syndrome 9SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009504

Submitter: Orphanet

mitochondrial DNA depletion syndrome 9STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009504

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Mitochondrial DNA depletion syndrome 9 (encephalomyopathic type with methylmalonic aciduria)AR

Manifestation: Biochemical; Musculoskeletal; 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: 17668387; 19526370; 20693550; 21093335; 21639866

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SUCLG1 variants in ClinVar

5 Conditions Cataloged

Mitochondrial DNA depletion syndrome 9Total: 277

not providedTotal: 80

Inborn genetic diseasesTotal: 44

not specifiedTotal: 33

SUCLG1-related disorderTotal: 19

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003849.4. 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	72 clinvar		77
missense	4 clinvar	11 clinvar	129 clinvar	10 clinvar		154
nonsense	9 clinvar	1 clinvar				10
start loss			2 clinvar			2
frameshift	6 clinvar	1 clinvar	2 clinvar			9
splice donor/acceptor (+/-2bp)	1 clinvar	5 clinvar				6
Total	20	18	138	82	0	258

Highest pathogenic variant AF is 0.00003284007

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 31 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003849.4	RefSeq	NP_003840.2	9	MANE Select
ENST00000393868.7	Ensembl	ENSP00000377446.2	9	MANE Select
ENST00000442240.5	Ensembl	ENSP00000403884.1	4	Standard
ENST00000651342.1	Ensembl	ENSP00000498471.1	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Citrate cycle (TCA cycle) - Homo sapiens (human)
Propanoate metabolism - Homo sapiens (human)
Valproic Acid Pathway, Pharmacodynamics
Pathway_PA165964473
Warburg Effect

Biological Process

tricarboxylic acid cycle
succinyl-CoA metabolic process
succinate metabolic process
nucleoside diphosphate phosphorylation
nucleoside triphosphate biosynthetic process

Molecular Function

RNA binding
nucleoside diphosphate kinase activity
succinate-CoA ligase (ADP-forming) activity
cofactor binding

Cellular Component

mitochondrion
mitochondrial matrix
cytosol
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000393868
Coding exons: 9
Length: 36523
Individuals with no LoFs: 125727
Homozygous LoFs: 0
Heterozygous LoFs: 21
Defined: 125748
p: 0.0000835

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.217	199	191	1.04	0.00000980	2229
Missense (PolyPhen)		73	79.789	0.91491		961
Synonymous	-0.132	72	70.6	1.02	0.00000384	708
Loss of Function	1.94	8	16.5	0.485	8.11e-7	200

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00016	0.00016	rare
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.00011	0.00011	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Succinyl-CoA synthetase functions in the citric acid cycle (TCA), coupling the hydrolysis of succinyl-CoA to the synthesis of either ATP or GTP and thus represents the only step of substrate-level phosphorylation in the TCA. The alpha subunit of the enzyme binds the substrates coenzyme A and phosphate, while succinate binding and specificity for either ATP or GTP is provided by different beta subunits. {ECO:0000255|HAMAP- Rule:MF_03222}.;
Disease: DISEASE: Mitochondrial DNA depletion syndrome 9 (MTDPS9) [MIM:245400]: A severe disorder due to mitochondrial dysfunction. It is characterized by infantile onset of hypotonia, lactic acidosis, severe psychomotor retardation, progressive neurologic deterioration, and excretion of methylmalonic acid. {ECO:0000269|PubMed:17668387, ECO:0000269|PubMed:19526370, ECO:0000269|PubMed:20453710, ECO:0000269|PubMed:20693550}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.535

Intolerance Scores

LoFtool: 0.235
RVIS EVS: -0.47
RVIS percentile EVS: 23.25

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.987

Gene Damage Prediction

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