SDHAF1

protein-coding

succinate dehydrogenase complex assembly factor 1, the group of LYR motif containing|Mitochondrial respiratory chain complex assembly factors

Gene summary

The succinate dehydrogenase (SDH) complex (or complex II) of the mitochondrial respiratory chain is composed of 4 individual subunits. The protein encoded by this gene resides in the mitochondria, and is essential for SDH assembly, but does not physically associate with the complex in vivo. Mutations in this gene are associated with SDH-defective infantile leukoencephalopathy (mitochondrial complex II deficiency).[provided by RefSeq, Mar 2010]

MANE transcript

NM_001042631.3

Inheritance

ClinVar variants

P:8U:49B:20

Top phenotype

Mitochondrial complex II deficiency, nuclear type 2

gnomAD constraint

pLI —, LoF o/e 1.11

Max pathogenic AF

—

Genomic locus

chr19:35,995,188-35,996,312

External References & Databases

Ensembl (ENSG00000205138)

Transcript & Mutation Effects

hg38 • Region Span ~1.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mitochondrial complex 2 deficiency, nuclear type 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0030935

Submitter: G2P

mitochondrial complex II deficiency, nuclear type 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0100294

Submitter: Labcorp Genetics (formerly Invitae)

mitochondrial complex II deficiencyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009641

Submitter: Ambry Genetics

Leigh syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between SDHAF1 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of January 13, 2020. The SDHAF1 gene encodes succinate dehydrogenase (complex II) assembly factor 1. The SDHAF1 gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2009 (PMID: 19465911). Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. This curation included one homozygous variant identified in one case in one publication (PMID: 19465911). Segregation data includes 4 affected individuals and 12 unaffected individuals in one kindred (PMID: 19465911). Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by functional alteration in patient cells (PMIDs: 19465911, 22995659). In summary, there is limited evidence to support this gene-disease relationship. 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 U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on January 13, 2020 (SOP Version 7).

mitochondrial complex 2 deficiency, nuclear type 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030935

Submitter: PanelApp Australia

mitochondrial complex II deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009641

Submitter: Orphanet

mitochondrial diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *SDHAF1* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of December 4, 2023. The *SDHAF1* gene encodes succinate dehydrogenase (complex II) assembly factor 1. Defects of this protein have been associated with autosomal recessive complex II deficiency. The *SDHAF1* gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2009 (PMID: 19465911), in one family with features consistent with Leigh syndrome spectrum (LSS) and in another family with leukoencephalopathy. While various names have been given to the constellation of features seen in those with *SDHAF1*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *SDHAF1* phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, *SDHAF1* was previously curated by this GCEP on January 13, 2020 (SOP Version 7) as having a limited association with LSS. The scope of this current curation encompassed cases of primary mitochondrial disease, which includes LSS. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included six unique variants (three missense, three stop-gained variants) from four publications (PMIDs: 19465911, 22995659, 31130284, 26642834). In addition to LSS and leukoencephalopathy, affected individuals also had spastic paraplegia, dystonia, failure to thrive, and sensorineural hearing loss. Muscle biopsies showed complex II deficiency. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease, yeast knockdown showing complex II deficiency, and rescue of complex II activity in patient cells by wild-type protein (PMIDs: 19465911, 26749241, 33162331). In summary, there is definitive evidence to support this gene-disease relationship, including that more than three years have elapsed since the first proposal of the association. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. 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 December 4, 2023 (SOP Version 10).

Clinical Genomic Database (CGD)

Mitochondrial complex II deficiency, nuclear type 2AR

Manifestation: Biochemical; Cardiovascular; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: Biochemical; Cardiovascular

Rationale: Medical treatment (eg, riboflavin, ubiquinol) may be beneficial; Individuals may multisystemic, including cardiac, involvemen (which can include arrhythmias), and surveillance and early interventions may be beneficial

Refs: 12112045; 16737791; 19465911; 22995659; 23322652

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SDHAF1 variants in ClinVar

6 Conditions Cataloged

not providedTotal: 37

Inborn genetic diseasesTotal: 36

Mitochondrial complex 2 deficiency, nuclear type 2Total: 10

Mitochondrial complex II deficiency, nuclear type 1Total: 8

not specifiedTotal: 7

SDHAF1-related disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001042631.3. 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			1 clinvar	17 clinvar		18
missense	2 clinvar	2 clinvar	47 clinvar	3 clinvar		54
nonsense	1 clinvar	2 clinvar				3
start loss		1 clinvar	1 clinvar			2
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	3	5	49	20	0	77

Highest pathogenic variant AF is 0.0000158078

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 2 of 2 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001042631.3	RefSeq	NP_001036096.2	1	MANE Select
ENST00000378887.4	Ensembl	ENSP00000368165.2	1	MANE Select

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

mitochondrial respiratory chain complex II assembly

Molecular Function

protein binding

Cellular Component

mitochondrion
mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000378887
Coding exons: 1
Length: 1131
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.379	49	57.1	0.859	0.00000286	681
Missense (PolyPhen)		16	19.595	0.81653		223
Synonymous	0.936	21	27.2	0.772	0.00000137	259
Loss of Function	-0.0930	1	0.905	1.11	3.87e-8	8

Population LoF Frequency

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

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plays an essential role in the assembly of succinate dehydrogenase (SDH), an enzyme complex (also referred to as respiratory complex II) that is a component of both the tricarboxylic acid (TCA) cycle and the mitochondrial electron transport chain, and which couples the oxidation of succinate to fumarate with the reduction of ubiquinone (coenzyme Q) to ubiquinol. Promotes maturation of the iron-sulfur protein subunit SDHB of the SDH catalytic dimer, protecting it from the deleterious effects of oxidants. May act together with SDHAF3. {ECO:0000269|PubMed:19465911, ECO:0000269|PubMed:24954417}.;

Essentials

Essential (CRISPR): E
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.448

Gene Damage Prediction

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