PET100

protein-coding

PET100 cytochrome c oxidase chaperone, the group of Mitochondrial respiratory chain complex assembly factors

Gene summary

Mitochondrial complex IV, or cytochrome c oxidase, is a large transmembrane protein complex that is part of the respiratory electron transport chain of mitochondria. The small protein encoded by this gene plays a role in the biogenesis of mitochondrial complex IV. This protein localizes to the inner mitochondrial membrane and is exposed to the intermembrane space. Mutations in this gene are associated with mitochondrial complex IV deficiency. This gene has a pseudogene on chromosome 3. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2014]

Previous symbols:

C19orf79

MANE transcript

NM_001171155.2

Inheritance

ClinVar variants

P:11U:28B:19

Top phenotype

Mitochondrial complex IV deficiency, nuclear type 12

gnomAD constraint

pLI —, LoF o/e 1.03

Max pathogenic AF

—

Genomic locus

chr19:7,629,788-7,631,956

External References & Databases

Ensembl (ENSG00000229833)

NCBI Gene (100131801)

Transcript & Mutation Effects

hg38 • Region Span ~2.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mitochondrial diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *PET100* and *PET100*-related primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of October 17, 2024. The *PET100* gene encodes a protein with essential roles in complex IV assembly and maturation. The *PET100* gene was first reported in relation to autosomal recessive *PET100*-related primary mitochondrial disease in 2014 (PMID: 24462369). *PET100* has been associated with a single disease entity to date; mitochondrial complex IV deficiency, nuclear type 12 [OMIM# 619055]. This is one disease entity according to the ClinGen Lumping and Splitting Framework, and has been renamed as *PET100*-related primary mitochondrial disease. Of note, *PET100* was first curated by this Expert Panel for its association with Leigh syndrome spectrum (LSS) on May 13, 2019 (SOP v6), with a final classification of Moderate. This current curation for the association with *PET100*-related primary mitochondrial disease includes cases with LSS. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included two unique variants (Lebanese founder start loss variant and a nonsense variant) identified in eight unrelated cases from four publications (PMIDs: 24462369, 31406627, 25293719, 32313153). Onset is in the first few months of life. Clinical features in affected individuals include LSS, seizures, dystonia, microcephaly, spasticity, feeding difficulty, short stature, respiratory failure, cardiomyopathy, and lactic acidosis. Complex IV deficiency is seen in skeletal muscle and skin fibroblasts. The mechanism of disease is loss of function. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease (PMID: 33340416), functional alteration studies in patient cells (PMID: 25293719), rescue in patient cells (PMID: 24462369), and a yeast model (PMID: 8702496). In summary, there is definitive evidence to support the relationship between *PET100* and autosomal recessive *PET100*-related primary mitochondrial disease. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on October 17, 2024 (SOP Version 10).

mitochondrial complex IV deficiency, nuclear type 12STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0033646

Submitter: G2P

mitochondrial complex IV deficiency, nuclear type 12STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0033646

Submitter: PanelApp Australia

mitochondrial complex IV deficiency, nuclear type 12STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0033646

Submitter: Ambry Genetics

Leigh syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between PET100 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of May 13, 2019. 4 articles were reviewed. PET100 was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2014 (Lim et al., PMID: 24462369). Two unique variants predicted to cause a loss of or reduced function of the protein have been reported in ClinVar. Complex IV deficiency is the disease mechanism 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 7 probands with Leigh syndrome spectrum in 1 publication (PMID 24462369). This gene-disease association is further supported by the function of the gene product and studies in patient cell lines. In summary, there is moderate evidence to support the relationship between PET100 and autosomal recessive Leigh syndrome spectrum. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on May 13, 2019 (SOP Version 6).

cytochrome-c oxidase deficiency diseaseSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009068

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Mitochondrial complex IV deficiency, nuclear type 12AR

Manifestation: Biochemical; Musculoskeletal; Neurologic; Ophthalmologic

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: 24462369

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PET100 variants in ClinVar

8 Conditions Cataloged

not providedTotal: 77

Mitochondrial complex IV deficiency, nuclear type 12Total: 21

Inborn genetic diseasesTotal: 14

not specifiedTotal: 7

PET100-related disorderTotal: 5

Mitochondrial complex IV deficiency, nuclear type 1Total: 3

Abnormality of the mitochondrionTotal: 1

Congenital lactic acidosisTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001171155.2. 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				11 clinvar		11
missense			24 clinvar	7 clinvar	1 clinvar	32
nonsense	2 clinvar	1 clinvar	1 clinvar			4
start loss	2 clinvar	2 clinvar				4
frameshift						0
splice donor/acceptor (+/-2bp)		4 clinvar	3 clinvar			7
Total	4	7	28	18	1	58

Highest pathogenic variant AF is 0.000042611646

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 27 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001171155.2	RefSeq	NP_001164626.1	4	MANE Select
ENST00000594797.6	Ensembl	ENSP00000470539.1	4	MANE Select
ENST00000456958.7	Ensembl	ENSP00000392303.3	3	Standard
ENST00000456958.8	Ensembl	ENSP00000392303.3	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

mitochondrial respiratory chain complex IV assembly

Molecular Function

unfolded protein binding

Cellular Component

integral component of mitochondrial inner membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000594797
Coding exons: 4
Length: 2220
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	0.242	38	42.4	0.895	0.00000272	477
Missense (PolyPhen)		0	0.88583	0		12
Synonymous	1.37	8	14.7	0.544	9.41e-7	122
Loss of Function	-0.0597	5	4.86	1.03	2.08e-7	54

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

Intolerance Scores

RVIS EVS: 0.63
RVIS percentile EVS: 83.59

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): K

Gene Damage Prediction

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