PCCA

protein-coding

propionyl-CoA carboxylase subunit alpha

Gene summary

The protein encoded by this gene is the alpha subunit of the heterodimeric mitochondrial enzyme Propionyl-CoA carboxylase. PCCA encodes the biotin-binding region of this enzyme. Mutations in either PCCA or PCCB (encoding the beta subunit) lead to an enzyme deficiency resulting in propionic acidemia. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, May 2010]

MANE transcript

NM_000282.4

Inheritance

ClinVar variants

P:333U:433B:359

Top phenotype

Propionic acidemia

gnomAD constraint

pLI —, LoF o/e 0.67

Max pathogenic AF

—

Genomic locus

chr13:100,089,015-100,530,437

External References & Databases

Ensembl (ENSG00000175198)

Transcript & Mutation Effects

hg38 • Region Span ~441.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

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 PCCA and propionic acidemia (autosomal recessive) was evaluated using the ClinGen Clinical Validity Framework as of November 28th, 2018. PCCA encodes the alpha subunit of propionyl-CoA carboxylase (PCC). PCC is composed of 6 alpha-subunit and 6 beta-subunits. The beta subunit is encoded by PCCB. 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 PCCA were first reported in humans with this disease as early as 1996 (Campeau et al, Am J Hum Genet 59 (suppl 59): A1448; Richard et al, 1997, PMID 9385377). At least 9 unique variants (missense, nonsense, frameshift, and splice site) 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 8 probands in 4 publications (Richard et al, 1997, PMID 9385377; Yang et al, 2004, PMID 15059621; Vatanavicharn et al, 2014, PMID 24464666; 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 PCCA as a subunit of PCC (see Wongkittichote et al, 2017, PMID 29033250 for review), the finding that variants in the gene encoding the beta subunit of PCC (PCCB) cause propionic acidemia, genetic complementation studies (Gravel et al, 1997, PMID 195466), a null mouse model which recapitulates the biochemical features of propionic acidemia, and rescue of the phenotype in the null mouse model by a Pcca transgene (Miyazaki et al, 2001; PMID 11461925) and AAV8 Pcca gene transfer (Chandler et al, 2011; PMID 20950151). In summary, PCCA 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: Natera

propionic acidemiaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011628

Submitter: Myriad Women's Health

propionic acidemiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011628

Submitter: Orphanet

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: 4815259; 10502773; 17051315; 19157943; 20301313; 22033733; 22593918 ; 23053474; 30879957; 36395710; 38570682

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PCCA variants in ClinVar

8 Conditions Cataloged

Propionic acidemiaTotal: 1421

not providedTotal: 155

Inborn genetic diseasesTotal: 100

not specifiedTotal: 99

PCCA-related disorderTotal: 40

Inborn errors of metabolismTotal: 1

Pontocerebellar hypoplasia type 2DTotal: 1

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000282.4. 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	20 clinvar	338 clinvar		360
missense	7 clinvar	50 clinvar	404 clinvar	18 clinvar	3 clinvar	482
nonsense	29 clinvar	20 clinvar	2 clinvar			51
start loss	1 clinvar	2 clinvar	1 clinvar			4
frameshift	60 clinvar	72 clinvar	2 clinvar			134
splice donor/acceptor (+/-2bp)	12 clinvar	78 clinvar	4 clinvar			94
Total	109	224	433	356	3	1125

Highest pathogenic variant AF is 0.00009029159

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 159 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000282.4	RefSeq	NP_000273.2	24	MANE Select
ENST00000376285.6	Ensembl	ENSP00000365462.1	24	MANE Select
NM_001127692.3	RefSeq	NP_001121164.1	23	Standard
NM_001178004.2	RefSeq	NP_001171475.1	23	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
biotin binding
enzyme binding

Cellular Component

mitochondrial matrix
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000376285
Coding exons: 24
Length: 441418
Individuals with no LoFs: 125628
Homozygous LoFs: 0
Heterozygous LoFs: 120
Defined: 125748
p: 0.000477

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.185	387	397	0.974	0.0000212	4736
Missense (PolyPhen)		99	136.3	0.72634		1604
Synonymous	0.911	127	141	0.902	0.00000793	1375
Loss of Function	2.06	30	44.9	0.668	0.00000225	551

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00061	0.00061	rare
Ashkenazi Jewish	0.00080	0.00079	rare
East Asian	0.00038	0.00038	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00046	0.00046	rare
South Asian	0.00075	0.00075	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Disease: DISEASE: Propionic acidemia type I (PA-1) [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:10101253, ECO:0000269|PubMed:10329019, ECO:0000269|PubMed:12559849, ECO:0000269|PubMed:15059621}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.427

Intolerance Scores

LoFtool: 0.116
RVIS EVS: 0.09
RVIS percentile EVS: 60.65

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.860

Gene Damage Prediction

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