PCCB

protein-coding

propionyl-CoA carboxylase subunit beta

Gene summary

The protein encoded by this gene is a subunit of the propionyl-CoA carboxylase (PCC) enzyme, which is involved in the catabolism of propionyl-CoA. PCC is a mitochondrial enzyme that probably acts as a dodecamer of six alpha subunits and six beta subunits. This gene encodes the beta subunit of PCC. Defects in this gene are a cause of propionic acidemia type II (PA-2). Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, May 2010]

MANE transcript

NM_000532.5

Inheritance

ClinVar variants

P:304U:365B:321

Top phenotype

Propionic acidemia

gnomAD constraint

pLI —, LoF o/e 0.6

Max pathogenic AF

—

Genomic locus

chr3:136,250,340-136,337,896

External References & Databases

Ensembl (ENSG00000114054)

Transcript & Mutation Effects

hg38 • Region Span ~87.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

propionic acidemiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011628

Submitter: Orphanet

propionic acidemiaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011628

Submitter: Natera

propionic acidemiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011628

Submitter: PanelApp Australia

propionic acidemiaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011628

Submitter: G2P

propionic acidemiaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011628

Submitter: ClinGen

The relationship between PCCB and propionic acidemia (autosomal recessive) was evaluated using the ClinGen Clinical Validity Framework as of November 28th, 2018. PCCB encodes the beta subunit of propionyl-CoA carboxylase (PCC). PCC is composed of 6 alpha-subunit and 6 beta-subunits. The alpha subunit is encoded by PCCA. PCC, a mitochondrial biotin-dependent enzyme, catalyzes the carboxylation of propionyl-CoA, which is produced by the catabolism of cholesterol, valine, odd chain fatty acids, methionine, isoleucine and threonine, to methylmalonyl-CoA. Variants in PCCB were first reported in humans with this disease as early as 1990 (Tahara et al, PMID 2154743). At least 13 unique variants (missense, nonsense, frameshift, splice site, and large deletion) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level and experimental data. Variants in this gene have been reported in at least 14 probands in 4 publications (Tahara et al, 1990, PMID 2154743; Tahara et al, 1993, PMID 8411997; Chiu et al, 2014, PMID 24863100; Gupta et al, 2016, PMID 27227689). Many more patients have been reported in the literature, but the maximum score for genetic evidence has been reached. The mechanism for disease is biallelic loss of function. This gene-disease association is supported by the biochemical function of PCCB as a subunit of PCC (see Wongkittichote et al, 2017, PMID 29033250 for review), the finding that variants in the gene encoding the alpha subunit of PCC (PCCA) cause propionic acidemia, genetic complementation studies (Gravel et al, 1997; PMID 195466; Rodríguez-Pombo et al, 2005, PMID 15949719), and rescue of PCC function in fibroblasts from patients with propionic acidemia by PCCB cDNA (Lamhonwah et al, 1994, PMID 8188292). In summary, PCCB is definitively associated with propionic acidemia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel.

propionic acidemiaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011628

Submitter: Myriad Women's Health

propionic acidemiaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011628

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

propionic acidemiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011628

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Propionic acidemiaAR

Manifestation: Allergy/Immunology/Infectious; Biochemical; Cardiovascular; Hematologic; Neurologic

Intervention: Biochemical; Cardiovascular

Rationale: In acute episodes, acidosis and hypoglycemia correction, with IV carnitine are beneficial (hemodialysis may be required); Dietary (including protein restriction, to decrease propiogenic substrates) and medical (eg, l-carnitine, metronidazole, N-carbamoylglutamate) therapy may be beneficial; Liver transplant may be required in some individuals; Fasting should be avoided, and care should be taken in the setting of acute stressors; Individuals are at risk for manifestations such as cardiovascular aberrations, and surveillance may be beneficial; mRNA therapy has shown promise in trials

Refs: 10502773; 17051315; 19238581; 20301313; 22593918; 22033733; 23053474; 30879957; 36395710; 38570682

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PCCB variants in ClinVar

9 Conditions Cataloged

Propionic acidemiaTotal: 1235

not providedTotal: 148

not specifiedTotal: 99

Inborn genetic diseasesTotal: 85

PCCB-related disorderTotal: 54

HyperammonemiaTotal: 2

Global developmental delayTotal: 2

Abnormality of metabolism/homeostasisTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000532.5. 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			12 clinvar	300 clinvar		312
missense	16 clinvar	77 clinvar	345 clinvar	19 clinvar	1 clinvar	458
nonsense	22 clinvar	16 clinvar	1 clinvar			39
start loss	5 clinvar	2 clinvar				7
frameshift	56 clinvar	44 clinvar	2 clinvar			102
splice donor/acceptor (+/-2bp)	12 clinvar	54 clinvar	5 clinvar	1 clinvar		72
Total	111	193	365	320	1	990

Highest pathogenic variant AF is 0.00019391756

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 82 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000532.5	RefSeq	NP_000523.2	15	MANE Select
ENST00000251654.9	Ensembl	ENSP00000251654.4	15	MANE Select
NM_001178014.2	RefSeq	NP_001171485.1	16	Standard
ENST00000459873.1	Ensembl	ENSP00000419293.1	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Propanoate metabolism - Homo sapiens (human)
Valine, leucine and isoleucine degradation - Homo sapiens (human)
Glyoxylate and dicarboxylate metabolism - Homo sapiens (human)
3-Methylglutaconic Aciduria Type I
Valine, Leucine and Isoleucine Degradation

Biological Process

biotin metabolic process

Molecular Function

propionyl-CoA carboxylase activity
protein binding
ATP binding

Cellular Component

mitochondrion
mitochondrial matrix
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000469217
Coding exons: 16
Length: 87591
Individuals with no LoFs: 125672
Homozygous LoFs: 0
Heterozygous LoFs: 76
Defined: 125748
p: 0.000302

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.867	353	310	1.14	0.0000172	3623
Missense (PolyPhen)		137	136.23	1.0056		1609
Synonymous	-1.67	139	116	1.20	0.00000658	1118
Loss of Function	2.00	17	28.5	0.596	0.00000159	331

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0012	0.0012	notable
Latino/Admixed American	0.00029	0.00029	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00033	0.00033	rare
Finnish	0.00018	0.00018	rare
European (Non-Finnish)	0.00027	0.00027	rare
South Asian	0.00016	0.00016	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Disease: DISEASE: Propionic acidemia type II (PA-2) [MIM:606054]: Life- threatening disease characterized by episodic vomiting, lethargy and ketosis, neutropenia, periodic thrombocytopenia, hypogammaglobulinemia, developmental retardation, and intolerance to protein. {ECO:0000269|PubMed:10447268, ECO:0000269|PubMed:11749052, ECO:0000269|PubMed:12189489, ECO:0000269|PubMed:12559849, ECO:0000269|PubMed:15059621, ECO:0000269|PubMed:2154743, ECO:0000269|PubMed:8411997, ECO:0000269|PubMed:9683601}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.542

Intolerance Scores

LoFtool: 0.0993
RVIS EVS: 0.11
RVIS percentile EVS: 62

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.994

Gene Damage Prediction

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