SDHAF2

protein-coding

succinate dehydrogenase complex assembly factor 2, the group of Mitochondrial respiratory chain complex assembly factors

Gene summary

This gene encodes a mitochondrial assembly factor needed for the flavination of a succinate dehydrogenase complex subunit (SDHA), which is required for activity of the succinate dehydrogenase complex. Mutations in this gene are associated with paraganglioma. [provided by RefSeq, May 2022]

Previous symbols:

PGL2
C11orf79

MANE transcript

NM_017841.4

Inheritance

ClinVar variants

P:69U:410B:158

Top phenotype

Pheochromocytoma/paraganglioma syndrome 2

gnomAD constraint

pLI —, LoF o/e 1.11

Max pathogenic AF

—

Genomic locus

chr11:61,430,042-61,446,839

External References & Databases

Ensembl (ENSG00000167985)

Transcript & Mutation Effects

hg38 • Region Span ~16.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

pheochromocytoma/paraganglioma syndrome 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011121

Submitter: Labcorp Genetics (formerly Invitae)

hereditary pheochromocytoma-paragangliomaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017366

Submitter: Orphanet

hereditary pheochromocytoma-paragangliomaDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017366

Submitter: ClinGen

Hereditary Paraganglioma-Pheochromocytoma Syndromes (PGL/PCC) [MONDO:0017366, PMID: 20301715] are associated with an increased risk of multiple paragangliomas and pheochromocytomas tumors within multiple organ systems transmitted in autosomal dominant inheritance. The molecular mechanism is loss of function in one of the 4 genes comprising the succinate dehydrogenase and SDHAF gene for flavination of SDHA, and stabilization of the SDH complex. This is a curation for SDHAF2 and SDHAF2 associated Hereditary Paraganglioma-Pheochromocytoma syndromes (PGL/PCC) (Paraganglioma 2, MIM: 601650). SDHAF2 was first reported in relation to PGL/PCC in 2009 [Hao et al., PMID: 19628817]. SDHAF2 related hereditary PGL/PCC syndromes are rare and only account for less than 0.1% of the cases with PGL/PCC. A Dutch founder variant in exon 2 of SDHAF2 gene, NM_017841.2(SDHAF2):c.232G>A (p.Gly78Arg), was identified in a large Dutch family via linkage study over a 30 years of period, which showed a parent-of-origin effect [PMIDs: 19628817, 6286462, 7814027, 8388849, 21224366]. Evidence suggests that this pathogenic variant in exon 2 of SDHAF2 destabilizes the protein, impairing its interaction with SDHA [PMID: 19628817]. This variant was also reported in a small Spanish family [PMID: 20071235], and sporadic cases [PMID: 28384794]. A variant at the same codon, but with different nucleotide change, NM_017841.4:c.232G>C p.Gly78Arg, was reported in a sporadic case from a cohort of 79 patients [PMID: 22241717]. Another missense variant and three nonsense variants are included in this curation [PMIDs: 26096992, 26269449, 22241717]. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. Experimental evidence is mainly from a comprehensive study on the p.Gly78Arg Dutch founder variant [PMID: 19628817]. The SDHA flavination was decreased which results from impaired interaction with SDHA in patients’ tumor cells. In yeast model, wt hSDHAF2 can rescue growth defects by increasing the falvination in the model with yeast sdh5 deletion, but this missense variant had no such rescuing effect. Other studies in yeast also indicated mutations in yeast sdh5 disrupt the covalent flavination of sdh1 [PMID: 23062074]. In summary, SDHAF2 gene is definitely associated with autosomal dominant HPGL/PCC syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.

pheochromocytoma/paraganglioma syndrome 2MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0011121

Submitter: Ambry Genetics

pheochromocytoma/paraganglioma syndrome 2DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011121

Submitter: G2P

Clinical Genomic Database (CGD)

Pheochromocytoma/paraganglioma syndrome 2AD

Manifestation: Oncologic

Intervention: Oncologic

Rationale: The condition involves increased risk of certain types of neoplasms, and surveillance/early treatment of tumors (eg, surgical resection) may be beneficial

Refs: 6286462; 19628817; 20071235; 21348866; 20301715; 21224366; 22584701; 23061808; 23078982

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SDHAF2 variants in ClinVar

8 Conditions Cataloged

Hereditary pheochromocytoma and paragangliomaTotal: 534

Hereditary cancer-predisposing syndromeTotal: 495

not providedTotal: 110

Pheochromocytoma/paraganglioma syndrome 2Total: 77

not specifiedTotal: 27

SDHAF2-related disorderTotal: 24

Ovarian cancerTotal: 3

Inherited phaeochromocytoma and paraganglioma excluding NF1Total: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_017841.4. 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			6 clinvar	139 clinvar		145
missense	1 clinvar	4 clinvar	373 clinvar	18 clinvar	1 clinvar	397
nonsense	4 clinvar	13 clinvar	5 clinvar			22
start loss			5 clinvar			5
frameshift	15 clinvar	18 clinvar	12 clinvar			45
splice donor/acceptor (+/-2bp)	1 clinvar	13 clinvar	9 clinvar			23
Total	21	48	410	157	1	637

Highest pathogenic variant AF is 0.0000287306

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 46 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_017841.4	RefSeq	NP_060311.1	4	MANE Select
ENST00000301761.7	Ensembl	ENSP00000301761.3	4	MANE Select
ENST00000359614.9	Ensembl	ENSP00000352630.5	4	Standard
ENST00000536250.1	Ensembl	ENSP00000471120.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

tricarboxylic acid cycle
mitochondrial electron transport, succinate to ubiquinone
protein dephosphorylation
negative regulation of epithelial to mesenchymal transition
protein-FAD linkage

Molecular Function

protein binding

Cellular Component

nucleolus
mitochondrion
mitochondrial matrix
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000301761
Coding exons: 4
Length: 17488
Individuals with no LoFs: 125728
Homozygous LoFs: 0
Heterozygous LoFs: 20
Defined: 125748
p: 0.0000795

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.139	92	88.3	1.04	0.00000485	1092
Missense (PolyPhen)		32	30.644	1.0443		412
Synonymous	-0.747	37	31.7	1.17	0.00000153	309
Loss of Function	-0.284	8	7.18	1.11	3.09e-7	92

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
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)	0.00014	0.00014	rare
South Asian	0.000065	0.000065	rare
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. Required for flavinylation (covalent attachment of FAD) of the flavoprotein subunit SDHA of the SDH catalytic dimer. {ECO:0000255|HAMAP-Rule:MF_03057, ECO:0000269|PubMed:19628817}.;
Disease: DISEASE: Paragangliomas 2 (PGL2) [MIM:601650]: A neural crest tumor usually derived from the chromoreceptor tissue of a paraganglion. Paragangliomas can develop at various body sites, including the head, neck, thorax and abdomen. Most commonly, they are located in the head and neck region, specifically at the carotid bifurcation, the jugular foramen, the vagal nerve, and in the middle ear. {ECO:0000269|PubMed:19628817}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.107

Intolerance Scores

RVIS EVS: 0.01
RVIS percentile EVS: 54.95

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): K
Indispensability pred.: E
Indispensability score: 0.781

Gene Damage Prediction

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