CYC1

protein-coding

cytochrome c1, the group of Apoptosome|Mitochondrial complex III: ubiquinol-cytochrome c reductase complex subunits

Gene summary

This gene encodes a subunit of the cytochrome bc1 complex, which plays an important role in the mitochondrial respiratory chain by transferring electrons from the Rieske iron-sulfur protein to cytochrome c. Mutations in this gene may cause mitochondrial complex III deficiency, nuclear type 6. [provided by RefSeq, Dec 2013]

MANE transcript

NM_001916.5

Inheritance

ClinVar variants

P:2U:103B:36

Top phenotype

Mitochondrial complex III deficiency, nuclear, type 6

gnomAD constraint

pLI —, LoF o/e 0.28

Max pathogenic AF

—

Genomic locus

chr8:144,095,039-144,097,525

External References & Databases

Ensembl (ENSG00000179091)

Transcript & Mutation Effects

hg38 • Region Span ~2.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mitochondrial diseaseMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between* CYC1* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of March 21, 2022. The *CYC1* gene encodes a subunit of complex III and plays an important role in the mitochondrial respiratory chain by transferring electrons from the Rieske iron-sulfur protein (UQCRFS1) to cytochrome *c*. The *CYC1* gene was first reported in relation to autosomal recessive mitochondrial disease in 2013 (PMID:23910460). While various names have been given to the constellation of features seen in those with *CYC1*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the CYC1 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 two unique missense variants identified in three cases from two publications (PMIDs: 23910460, 27074787). The Mitochondrial Disease Gene Curation Expert Panel reviewed scoring guidance for homozygous variants in cases with consanguinity and decided that no scoring alteration was needed in these cases given (1) comprehensive analyses (exome sequencing) were performed, (2) homozygous variants are a common cause of mitochondrial disease, and (3) biochemical evidence in these cases supported a complex III defect. Individuals with *CYC1*-related mitochondrial disease reported in the literature had neonatal insulin-responsive hyperglycemia, stress/infection-induced metabolic acidosis, and hyperammonemia with or without hepatic failure (PMID: 27074787). A fourth case was reported with a homozygous missense variant in *CYC1*, and this individual had recurrent optic neuritis. However, this case was not included for scoring in this gene-disease curation as this individual had a markedly different phenotype to that reported in other affected individuals with *CYC1* variants and there was no evidence of complex III deficiency and/or other evidence to support the impact of the variant (PMID: 34252606). This gene-disease association is also supported by known biochemical function, functional alteration in patient cells, and rescue models in patient cells (PMIDs: 23910460, 28844695). In summary, there is moderate 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/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on March 21, 2022 (SOP Version 8).

mitochondrial complex III deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0015448

Submitter: Orphanet

mitochondrial complex III deficiency nuclear type 6DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014194

Submitter: G2P

mitochondrial complex III deficiency nuclear type 6LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0014194

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Mitochondrial complex III deficiency, nuclear, type 6AR

Manifestation: Biochemical

Intervention: Biochemical

Rationale: Individuals may present with episodes of acute metabolic decompensation, including hyperlactatemia, hyperammonemia, ketoacidosis and glucose instability, and awareness may allow rapid treatment, including with IV rehydration (and insulin therapy as required), as well as other biochemical interventions (eg, arginine and sodium benzoate)

Refs: 23910460

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CYC1 variants in ClinVar

4 Conditions Cataloged

not providedTotal: 117

not specifiedTotal: 71

CYC1-related disorderTotal: 8

Mitochondrial complex III deficiency nuclear type 6Total: 6

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001916.5. 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			3 clinvar	31 clinvar	2 clinvar	36
missense	2 clinvar		94 clinvar	3 clinvar		99
nonsense						0
start loss						0
frameshift			2 clinvar			2
splice donor/acceptor (+/-2bp)			4 clinvar			4
Total	2	0	103	34	2	141

Highest pathogenic variant AF is 0.000001368195

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 54 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001916.5	RefSeq	NP_001907.3	7	MANE Select
ENST00000318911.5	Ensembl	ENSP00000317159.4	7	MANE Select
ENST00000876790.1	Ensembl	ENSP00000546849.1	7	Standard
ENST00000876790.2	Ensembl	ENSP00000546849.1	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Cardiac muscle contraction - Homo sapiens (human)
Non-alcoholic fatty liver disease (NAFLD) - Homo sapiens (human)
Alzheimer,s disease - Homo sapiens (human)
Huntington,s disease - Homo sapiens (human)
Thermogenesis - Homo sapiens (human)

Biological Process

mitochondrial electron transport, ubiquinol to cytochrome c
response to glucagon
mitochondrial ATP synthesis coupled proton transport

Molecular Function

heme binding
electron transporter, transferring electrons within CoQH2-cytochrome c reductase complex activity
electron transporter, transferring electrons from CoQH2-cytochrome c reductase complex and cytochrome c oxidase complex activity
metal ion binding

Cellular Component

nucleus
mitochondrion
mitochondrial inner membrane
mitochondrial respiratory chain complex III
membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000318911
Coding exons: 7
Length: 2499
Individuals with no LoFs: 125717
Homozygous LoFs: 0
Heterozygous LoFs: 29
Defined: 125746
p: 0.000115

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.127	169	174	0.973	0.00000981	2039
Missense (PolyPhen)		55	63.278	0.86918		735
Synonymous	-2.33	99	73.6	1.35	0.00000425	699
Loss of Function	2.53	4	14.3	0.279	7.91e-7	157

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.00027	0.00023	rare
European (Non-Finnish)	0.00013	0.00013	rare
South Asian	0	0.0	absent
Other	0.00017	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: This is the heme-containing component of the cytochrome b-c1 complex, which accepts electrons from Rieske protein and transfers electrons to cytochrome c in the mitochondrial respiratory chain.;
Disease: DISEASE: Mitochondrial complex III deficiency, nuclear 6 (MC3DN6) [MIM:615453]: An autosomal recessive disorder caused by mitochondrial dysfunction. It is characterized by onset in early childhood of episodic acute lactic acidosis, ketoacidosis, and insulin-responsive hyperglycemia, usually associated with infection. Laboratory studies show decreased activity of mitochondrial complex III. Psychomotor development is normal. {ECO:0000269|PubMed:23910460}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.223

Intolerance Scores

LoFtool: 0.214
RVIS EVS: -0.25
RVIS percentile EVS: 35.99

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.869

Gene Damage Prediction

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