PMPCB

protein-coding

peptidase, mitochondrial processing subunit beta, the group of M16 metallopeptidases

Gene summary

This gene is a member of the peptidase M16 family and encodes a protein with a zinc-binding motif. This protein is located in the mitochondrial matrix and catalyzes the cleavage of the leader peptides of precursor proteins newly imported into the mitochondria, though it only functions as part of a heterodimeric complex. [provided by RefSeq, Jul 2008]

MANE transcript

NM_004279.3

Inheritance

ClinVar variants

P:13U:101B:39

Top phenotype

Multiple mitochondrial dysfunctions syndrome 6

gnomAD constraint

pLI —, LoF o/e 0.59

Max pathogenic AF

—

Genomic locus

chr7:103,297,407-103,331,818

External References & Databases

Ensembl (ENSG00000105819)

Transcript & Mutation Effects

hg38 • Region Span ~34.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

multiple mitochondrial dysfunctions syndrome 6MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0054785

Submitter: Ambry Genetics

multiple mitochondrial dysfunctions syndrome 6STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0054785

Submitter: Labcorp Genetics (formerly Invitae)

multiple mitochondrial dysfunctions syndrome 6STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0054785

Submitter: PanelApp Australia

multiple mitochondrial dysfunctions syndrome 6MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0054785

Submitter: Illumina

The PMPCB gene is located on chromosome 7 at 7q22.1 and encodes the mitochondrial processing beta peptidase, which is the catalytic subunit of mitochondrial processing protease (MPP) and is required for proteolytic processing of mitochondrial proteins. The PMPCB gene was first reported in relation to autosomal recessive PMPCB-related multiple mitochondrial dysfunctions syndrome in 2018 (29576218: Vögtle et al. 2018). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Five missense variants in this gene have been reported in a compound heterozygous or homozygous state in four unrelated probands in one publication (29576218: Vögtle et al. 2018). The clinical phenotype was characterized by neurodegeneration in childhood with cerebellar atrophy. The proposed disease mechanism is that biallelic variants in PMPCB cause defects in MPP proteolytic activity and leads to dysregulation of iron-sulfur (Fe-S) cluster biogenesis. The gene-disease relationship is supported by biochemical function data and functional alteration in yeast and patient cells (25970558: Quiros et al. 2015; 29576218: Vögtle et al. 2018). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.

multiple mitochondrial dysfunctions syndrome 6STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0054785

Submitter: G2P

Clinical Genomic Database (CGD)

Multiple mitochondrial dysfunctions syndrome 6AR

Manifestation: Biochemical

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: 29576218

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PMPCB variants in ClinVar

8 Conditions Cataloged

not providedTotal: 96

Inborn genetic diseasesTotal: 75

Multiple mitochondrial dysfunctions syndrome 6Total: 30

PMPCB-related disorderTotal: 16

not specifiedTotal: 7

PMPCB-related mitochondrial disorderTotal: 1

PMPCB-related ataxiaTotal: 1

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004279.3. 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			2 clinvar	24 clinvar	2 clinvar	28
missense	3 clinvar	3 clinvar	89 clinvar	11 clinvar	2 clinvar	108
nonsense		2 clinvar	1 clinvar			3
start loss						0
frameshift		4 clinvar	3 clinvar			7
splice donor/acceptor (+/-2bp)		1 clinvar	6 clinvar			7
Total	3	10	101	35	4	153

Highest pathogenic variant AF is 0.00007683338

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 66 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004279.3	RefSeq	NP_004270.2	13	MANE Select
ENST00000249269.9	Ensembl	ENSP00000249269.4	13	MANE Select
NM_001438231.1	RefSeq	NP_001425160.1	12	Standard
ENST00000428154.5	Ensembl	ENSP00000390035.1	12	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Metabolism of proteins
Transport of small molecules
Mitochondrial protein import
Mitochondrial calcium ion transport
Processing of SMDT1

Biological Process

protein processing involved in protein targeting to mitochondrion
mitochondrial calcium ion transmembrane transport

Molecular Function

endopeptidase activity
metalloendopeptidase activity
metal ion binding

Cellular Component

mitochondrion
mitochondrial inner membrane
mitochondrial processing peptidase complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000249269
Coding exons: 13
Length: 32090
Individuals with no LoFs: 125690
Homozygous LoFs: 0
Heterozygous LoFs: 58
Defined: 125748
p: 0.000231

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.216	279	269	1.04	0.0000135	3173
Missense (PolyPhen)		76	67.687	1.1228		815
Synonymous	-0.245	93	90.0	1.03	0.00000433	952
Loss of Function	1.96	16	27.0	0.592	0.00000139	333

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00031	0.00031	rare
Latino/Admixed American	0.00023	0.00020	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00022	0.00022	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00026	0.00025	rare
South Asian	0.00031	0.00029	rare
Other	0.00036	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalytic subunit of the essential mitochondrial processing protease (MPP), which is required for maturation of the majority of mitochondrial precursor proteins (PubMed:29576218). Most MPP cleavage sites follow an arginine at position -2 (By similarity). {ECO:0000250|UniProtKB:P20069, ECO:0000269|PubMed:29576218}.;
Disease: DISEASE: Multiple mitochondrial dysfunctions syndrome 6 (MMDS6) [MIM:617954]: An autosomal recessive, neurodegenerative disorder characterized by basal ganglia lesions, cerebellar atrophy, and neurologic regression in the first year of life. Common features include truncal hypotonia, lack of independent ambulation, poor speech, intellectual disability, and motor abnormalities, such as ataxia, dystonia, and spasticity. {ECO:0000269|PubMed:29576218}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.106

Intolerance Scores

LoFtool: 0.878
RVIS EVS: -0.42
RVIS percentile EVS: 25.73

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.631

Gene Damage Prediction

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