Human Gene Module / Chromosome 13 / PCCA

PCCApropionyl-CoA carboxylase alpha subunit

SFARI Gene Score
S
Syndromic Syndromic
Autism Reports / Total Reports
3 / 13
Rare Variants / Common Variants
20 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
13q32.3
Associated Disorders
DD/NDD, ASD
Relevance to Autism

A homozygous PCCA missense variant (p.Gly117Asp) was identified in a female Saudi patient with propionic acidemia and a DSM-IV diagnosis of autistic disorder (Al-Owain et al., 2013). Two additional patients with propionic acidemia caused by homozygous PCCA variants were reported to exhibit autistic features in 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 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 (OMIM 606054).

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to PCCA (13 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 Primary Autism spectrum disorder in a child with propionic acidemia Al-Owain M , et al. (2013) No ASD
4 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 -
5 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 -
6 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 -
7 Recent Recommendation Modulation of mitochondrial function by the microbiome metabolite propionic acid in autism and control cell lines Frye RE , et al. (2016) No -
8 Support Autism in patients with propionic acidemia Witters P , et al. (2016) No Autistic features
9 Support Clinical exome sequencing: results from 2819 samples reflecting 1000 families Trujillano D , et al. (2016) No DD, microcephaly, hypotonia
10 Support Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population Monies D , et al. (2019) Yes -
11 Support - Woodbury-Smith M et al. (2022) Yes -
12 Support - Cirnigliaro M et al. (2023) Yes -
13 Support - Oleg A Shchelochkov et al. (2024) No ASD, ID
Rare Variants   (20)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1209+3A>G - intron_variant - - - 27825584 Witters P , et al. (2016)
- - copy_number_loss Unknown - - 38200289 Oleg A Shchelochkov et al. (2024)
c.600+1G>A - splice_site_variant Unknown - - 38200289 Oleg A Shchelochkov et al. (2024)
c.716+5G>C - splice_site_variant Unknown - - 38200289 Oleg A Shchelochkov et al. (2024)
c.1284+1G>A - splice_site_variant Unknown - - 38200289 Oleg A Shchelochkov et al. (2024)
c.1891C>G p.Gly631Arg missense_variant - Both parents - 27825584 Witters P , et al. (2016)
c.2119-9A>G - splice_region_variant Unknown - - 38200289 Oleg A Shchelochkov et al. (2024)
c.1801C>T p.Pro601Ser missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.782A>G p.Glu261Gly missense_variant Unknown - - 38200289 Oleg A Shchelochkov et al. (2024)
c.802C>T p.Arg268Cys missense_variant Unknown - - 38200289 Oleg A Shchelochkov et al. (2024)
c.893A>G p.Lys298Arg missense_variant Unknown - - 38200289 Oleg A Shchelochkov et al. (2024)
c.1684T>C p.Ser562Pro missense_variant Unknown - - 38200289 Oleg A Shchelochkov et al. (2024)
c.1899+4_1899+7del - splice_site_variant Unknown - - 38200289 Oleg A Shchelochkov et al. (2024)
- p.Gly117Asp missense_variant Familial Both parents Simplex 23430497 Al-Owain M , et al. (2013)
c.425G>A p.Gly142Asp missense_variant Familial Both parents - 27848944 Trujillano D , et al. (2016)
c.2027del p.Lys676SerfsTer6 frameshift_variant Unknown - - 38200289 Oleg A Shchelochkov et al. (2024)
c.866_867del p.Glu289ValfsTer53 frameshift_variant Unknown - - 38200289 Oleg A Shchelochkov et al. (2024)
c.1899+4_1899+7del - splice_site_variant Familial Maternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.2162_2163insAG p.Asp722GlyfsTer32 frameshift_variant Unknown - - 38200289 Oleg A Shchelochkov et al. (2024)
c.5_24del p.Ala2GlyfsTer42 frameshift_variant Familial Both parents Simplex 31130284 Monies D , et al. (2019)
Common Variants  

No common variants reported.

SFARI Gene score
S

Syndromic

Biallelic variants in the PCCA gene are responsible for propionic acidemia (OMIM 606054). A homozygous PCCA missense variant (p.Gly117Asp) was identified in a female Saudi patient with propionic acidemia and a DSM-IV diagnosis of autistic disorder (Al-Owain et al., 2013). Two additional patients with propionic acidemia caused by homozygous PCCA variants were reported to exhibit autistic features in 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 S

criteria met
See SFARI Gene'scoring criteria
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."

10/1/2019
S
icon
S

Score remained at S

New Scoring Scheme
Description

Biallelic variants in the PCCA gene are responsible for propionic acidemia (OMIM 606054). A homozygous PCCA missense variant (p.Gly117Asp) was identified in a female Saudi patient with propionic acidemia and a DSM-IV diagnosis of autistic disorder (Al-Owain et al., 2013). Two additional patients with propionic acidemia caused by homozygous PCCA variants were reported to exhibit autistic features in 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

Score remained at S

Description

Biallelic variants in the PCCA gene are responsible for propionic acidemia (OMIM 606054). A homozygous PCCA missense variant (p.Gly117Asp) was identified in a female Saudi patient with propionic acidemia and a DSM-IV diagnosis of autistic disorder (Al-Owain et al., 2013). Two additional patients with propionic acidemia caused by homozygous PCCA variants were reported to exhibit autistic features in 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
[Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population.2019]
Krishnan Probability Score

Score 0.4164943067835

Ranking 21347/25841 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 2.1332473859349E-10

Ranking 16831/18225 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 0.94980491925755

Ranking 18239/18665 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 0.2032169754682

Ranking 4211/20870 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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