Human Gene Module / Chromosome 3 / PCCB

PCCBpropionyl-CoA carboxylase beta subunit

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
3 / 12
Rare Variants / Common Variants
27 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
3q22.3
Associated Disorders
ASD
Relevance to Autism

A diagnosis of autism according to either DSM-IV or DSM-5 criteria was made for four patients with propionic acidemia resulting from biallelic variants in the PCCB gene; one additional patient with a homozygous variant in this gene presented with autistic features (Witters et al., 2016). Administration of propionic acid to rats have been shown to induce autistic-like behaviors in multiple studies (MacFabe et al., 2007; MacFabe et al., 2011; Foley et al., 2014; Foley et al., 2014; Shultz et al., 2015).

Molecular Function

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; OMIM 606054).

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to PCCB (12 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Neurobiological effects of intraventricular propionic acid in rats: possible role of short chain fatty acids on the pathogenesis and characteristics of autism spectrum disorders MacFabe DF , et al. (2006) No -
2 Support Effects of the enteric bacterial metabolic product propionic acid on object-directed behavior, social behavior, cognition, and neuroinflammation in adolescent rats: Relevance to autism spectrum disorder MacFabe DF , et al. (2010) No -
3 Support Pre- and neonatal exposure to lipopolysaccharide or the enteric metabolite, propionic acid, alters development and behavior in adolescent rats in a sexually dimorphic manner Foley KA , et al. (2014) No -
4 Support Sexually dimorphic effects of prenatal exposure to propionic acid and lipopolysaccharide on social behavior in neonatal, adolescent, and adult rats: implications for autism spectrum disorders Foley KA , et al. (2014) No -
5 Support Intracerebroventricular injection of propionic acid, an enteric metabolite implicated in autism, induces social abnormalities that do not differ between seizure-prone (FAST) and seizure-resistant (SLOW) rats Shultz SR , et al. (2014) No -
6 Recent Recommendation Modulation of mitochondrial function by the microbiome metabolite propionic acid in autism and control cell lines Frye RE , et al. (2016) No -
7 Primary Autism in patients with propionic acidemia Witters P , et al. (2016) No ASD or autistic features
8 Support Clinical utility of exome sequencing in individuals with large homozygous regions detected by chromosomal microarray analysis Prasad A , et al. (2018) Yes -
9 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
10 Support - Zhou X et al. (2022) Yes -
11 Support - Amerh S Alqahtani et al. (2023) No -
12 Support - Oleg A Shchelochkov et al. (2024) No ASD, ID
Rare Variants   (27)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss Unknown - - 38200289 Oleg A Shchelochkov et al. (2024)
c.1426C>T p.Pro476Ser missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.337C>T p.Arg113Ter stop_gained Unknown - - 38200289 Oleg A Shchelochkov et al. (2024)
c.990dup p.Glu331Ter stop_gained Unknown - - 38200289 Oleg A Shchelochkov et al. (2024)
c.1495C>T p.Arg499Ter stop_gained Unknown - - 38200289 Oleg A Shchelochkov et al. (2024)
c.335G>A p.Gly112Asp missense_variant Unknown - - 38200289 Oleg A Shchelochkov et al. (2024)
c.734G>A p.Gly245Asp missense_variant Unknown - - 38200289 Oleg A Shchelochkov et al. (2024)
c.866G>C p.Arg289Pro missense_variant Unknown - - 38200289 Oleg A Shchelochkov et al. (2024)
c.479A>G p.Lys160Arg missense_variant Familial - Multiplex 27825584 Witters P , et al. (2016)
c.1606A>G p.Asn536Asp missense_variant Unknown - - 38200289 Oleg A Shchelochkov et al. (2024)
c.595C>T p.Pro199Ser missense_variant Familial Both parents - 29554876 Prasad A , et al. (2018)
c.337C>T p.Arg113Ter stop_gained Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.764-2del - splice_site_variant Unknown - Multiplex 38200289 Oleg A Shchelochkov et al. (2024)
c.562G>A p.Glu188Lys missense_variant Familial Both parents - 27825584 Witters P , et al. (2016)
c.683C>T p.Pro228Leu missense_variant Familial Both parents - 27825584 Witters P , et al. (2016)
c.975_977del p.Asp325del inframe_deletion Unknown - - 38200289 Oleg A Shchelochkov et al. (2024)
c.386_387delinsAAC p.Phe129Ter stop_gained Unknown - - 38200289 Oleg A Shchelochkov et al. (2024)
c.1225_1227del p.Ile409del inframe_deletion Unknown - - 38200289 Oleg A Shchelochkov et al. (2024)
c.76dup p.Arg26ProfsTer11 frameshift_variant Unknown - - 38200289 Oleg A Shchelochkov et al. (2024)
c.1204del p.Ala402HisfsTer41 frameshift_variant Unknown - - 38200289 Oleg A Shchelochkov et al. (2024)
c.1552del p.Asp518ThrfsTer33 frameshift_variant Unknown - - 38200289 Oleg A Shchelochkov et al. (2024)
c.683C>T p.Pro228Leu missense_variant Familial Both parents Multiplex 27825584 Witters P , et al. (2016)
c.975_977del p.Asp325del inframe_deletion Unknown - Multiplex 38200289 Oleg A Shchelochkov et al. (2024)
c.1172_1173del p.Phe391CysfsTer2 frameshift_variant Unknown - - 38200289 Oleg A Shchelochkov et al. (2024)
c.1050dup p.Glu351Ter frameshift_variant Familial Both parents Multiplex 37799141 Amerh S Alqahtani et al. (2023)
c.1218_1231delinsTAGAGCACAGGA p.Gly407ArgfsTer14 frameshift_variant Unknown - - 38200289 Oleg A Shchelochkov et al. (2024)
c.1218_1231delinsTAGAGCACAGGA p.Gly407ArgfsTer14 frameshift_variant Familial - Multiplex 27825584 Witters P , et al. (2016)
Common Variants  

No common variants reported.

SFARI Gene score
1S

High Confidence, Syndromic

Biallelic variants in the PCCB gene are responsible for propionic acidemia (OMIM 606054). A diagnosis of autism according to either DSM-IV or DSM-5 criteria was made for four patients with propionic acidemia resulting from biallelic variants in the PCCB gene; one additional patient with a homozygous variant in this gene presented with autistic features (Witters et al., 2016). Administration of propionic acid to rats have been shown to induce autistic-like behaviors in multiple studies (MacFabe et al., 2007; MacFabe et al., 2011; Foley et al., 2014; Foley et al., 2014; Shultz et al., 2015).

Score Delta: Score remained at 1S

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

4/1/2022
S
icon
1S

Increased from S to 1S

Description

Biallelic variants in the PCCB gene are responsible for propionic acidemia (OMIM 606054). A diagnosis of autism according to either DSM-IV or DSM-5 criteria was made for four patients with propionic acidemia resulting from biallelic variants in the PCCB gene; one additional patient with a homozygous variant in this gene presented with autistic features (Witters et al., 2016). Administration of propionic acid to rats have been shown to induce autistic-like behaviors in multiple studies (MacFabe et al., 2007; MacFabe et al., 2011; Foley et al., 2014; Foley et al., 2014; Shultz et al., 2015).

10/1/2019
S
icon
S

Increased from S to S

New Scoring Scheme
Description

Biallelic variants in the PCCB gene are responsible for propionic acidemia (OMIM 606054). A diagnosis of autism according to either DSM-IV or DSM-5 criteria was made for four patients with propionic acidemia resulting from biallelic variants in the PCCB gene; one additional patient with a homozygous variant in this gene presented with autistic features (Witters et al., 2016). Administration of propionic acid to rats have been shown to induce autistic-like behaviors in multiple studies (MacFabe et al., 2007; MacFabe et al., 2011; Foley et al., 2014; Foley et al., 2014; Shultz et al., 2015).

Reports Added
[New Scoring Scheme]
7/1/2019
S
icon
S

Increased from S to S

Description

Biallelic variants in the PCCB gene are responsible for propionic acidemia (OMIM 606054). A diagnosis of autism according to either DSM-IV or DSM-5 criteria was made for four patients with propionic acidemia resulting from biallelic variants in the PCCB gene; one additional patient with a homozygous variant in this gene presented with autistic features (Witters et al., 2016). Administration of propionic acid to rats have been shown to induce autistic-like behaviors in multiple studies (MacFabe et al., 2007; MacFabe et al., 2011; Foley et al., 2014; Foley et al., 2014; Shultz et al., 2015).

Reports Added
[Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.2019]
Krishnan Probability Score

Score 0.26766396545478

Ranking 25552/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.0007358394338912

Ranking 11981/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.93709509222186

Ranking 13411/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score 0.17030429389182

Ranking 4798/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
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