MIPEP

protein-coding

mitochondrial intermediate peptidase, the group of M3 metallopeptidase family

Gene summary

The product of this gene performs the final step in processing a specific class of nuclear-encoded proteins targeted to the mitochondrial matrix or inner membrane. This protein is primarily involved in the maturation of oxidative phosphorylation (OXPHOS)-related proteins. This gene may contribute to the functional effects of frataxin deficiency and the clinical manifestations of Friedreich ataxia. [provided by RefSeq, Jul 2008]

MANE transcript

NM_005932.4

Inheritance

ClinVar variants

P:23U:166B:90

Top phenotype

Combined oxidative phosphorylation deficiency 31

gnomAD constraint

pLI —, LoF o/e 0.76

Max pathogenic AF

—

Genomic locus

chr13:23,730,189-23,889,400

External References & Databases

Ensembl (ENSG00000027001)

Transcript & Mutation Effects

hg38 • Region Span ~159.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

lethal left ventricular non-compaction-seizures-hypotonia-cataract-developmental delay syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014976

Submitter: Broad Center for Mendelian Genomics

lethal left ventricular non-compaction-seizures-hypotonia-cataract-developmental delay syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014976

Submitter: Labcorp Genetics (formerly Invitae)

mitochondrial diseaseMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *MIPEP* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of February 6, 2023. The *MIPEP* gene encodes mitochondrial intermediate peptidase (MIP), a presequence protease which cleaves proteins that are imported into the mitochondrion to their mature size. The *MIPEP* gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2016 (PMID: 27799064), in four unrelated patients with a severe infantile onset disorder characterized by global developmental delay, seizures, hypotonia, hypertrophic cardiomyopathy, and left ventricular noncompaction (LVNC). While various names have been given to the constellation of features seen in those with *MIPEP*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *MIPEP* 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 14 unique variants (10 missense, one nonsense, one frameshift and two large deletions) reported in eight cases from five publications (PMIDs: 27799064, 35598585, 31607746, 27391121, 34620555). Subsequent publications have reported a consistent early-onset disease characterized by global developmental delay with or without a cardiac phenotype. Phenotypic heterogeneity is observed with additional features such as failure to thrive, feeding difficulties, optic atrophy, hypertonia, and microcephaly variably reported. When performed, muscle biopsies showed glycogen accumulation, lipid droplet accumulation within mitochondria, and abnormal mitochondrial morphology, as well as variable decreases in mitochondrial respiratory complex activities I, III and IV. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease and studies in patient fibroblast cells (PMIDs: 33340416, 34620555). In summary, there is moderate evidence to support the relationship between *MIPEP* and primary mitochondrial disease. 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 February 6, 2023 (SOP Version 9).

lethal left ventricular non-compaction-seizures-hypotonia-cataract-developmental delay syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014976

Submitter: PanelApp Australia

lethal left ventricular non-compaction-seizures-hypotonia-cataract-developmental delay syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014976

Submitter: Orphanet

Clinical Genomic Database (CGD)

Combined oxidative phosphorylation deficiency 31AR

Manifestation: Biochemical; Cardiovascular; Craniofacial; Neurologic; Ophthalmologic

Intervention: Cardiovascular

Rationale: The condition can include hypertrophic cardiomyopathy, and awareness may allow early diagnosis and interventions

Refs: 27799064

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MIPEP variants in ClinVar

10 Conditions Cataloged

not providedTotal: 184

Inborn genetic diseasesTotal: 121

not specifiedTotal: 71

Lethal left ventricular non-compaction-seizures-hypotonia-cataract-developmental delay syndromeTotal: 44

MIPEP-related disorderTotal: 15

CardiomyopathyTotal: 6

Left ventricular noncompactionTotal: 6

Floppy infantTotal: 6

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005932.4. 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			2 clinvar	61 clinvar	2 clinvar	65
missense		6 clinvar	152 clinvar	25 clinvar	2 clinvar	185
nonsense	3 clinvar	4 clinvar	1 clinvar			8
start loss		1 clinvar				1
frameshift		3 clinvar	4 clinvar			7
splice donor/acceptor (+/-2bp)	2 clinvar	4 clinvar	7 clinvar			13
Total	5	18	166	86	4	279

Highest pathogenic variant AF is 0.00014129459

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 42 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005932.4	RefSeq	NP_005923.3	19	MANE Select
ENST00000382172.4	Ensembl	ENSP00000371607.3	19	MANE Select
ENST00000906723.1	Ensembl	ENSP00000576782.1	19	Standard
ENST00000906723.2	Ensembl	ENSP00000576782.1	19	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

proteolysis
peptide metabolic process
protein processing involved in protein targeting to mitochondrion

Molecular Function

metalloendopeptidase activity
metal ion binding

Cellular Component

mitochondrion
mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000382172
Coding exons: 19
Length: 159231
Individuals with no LoFs: 125622
Homozygous LoFs: 0
Heterozygous LoFs: 126
Defined: 125748
p: 0.000501

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.222	366	378	0.968	0.0000205	4633
Missense (PolyPhen)		120	126.19	0.95094		1382
Synonymous	0.300	128	132	0.967	0.00000718	1350
Loss of Function	1.38	28	37.1	0.755	0.00000197	470

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00023	0.00023	rare
Ashkenazi Jewish	0.00012	0.000099	rare
East Asian	0.00034	0.00033	rare
Finnish	0.00018	0.00018	rare
European (Non-Finnish)	0.00066	0.00065	rare
South Asian	0.00078	0.00072	rare
Other	0.0011	0.0011	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Cleaves proteins, imported into the mitochondrion, to their mature size.;
Disease: DISEASE: Combined oxidative phosphorylation deficiency 31 (COXPD31) [MIM:617228]: An autosomal recessive, severe mitochondrial disease with multisystemic manifestations appearing soon after birth or in early infancy. Clinical features include left ventricular non-compaction, global developmental delay, severe hypotonia, seizures, cataract, and abnormal movements. Death may occur in early childhood. {ECO:0000269|PubMed:27799064}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.121

Intolerance Scores

LoFtool: 0.961
RVIS EVS: 0.62
RVIS percentile EVS: 83.53

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.552

Gene Damage Prediction

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