Human Gene Module / Chromosome 11 / PC

PCpyruvate carboxylase

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
8 / 8
Rare Variants / Common Variants
17 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
11q13.2
Associated Disorders
-
Relevance to Autism

De novo variants in the PC gene have been identified in ASD probands, including a de novo missense variant (p.Pro1042Arg) in a proband from the Simons Simplex Collection (Iossifov et al., 2014; Sanders et al., 2015; Yuen et al., 2016; Yuen et al., 2017; Turner et al., 2017). Targeted sequencing of 136 microcephaly or macrocephaly-related genes and 158 possible ASD risk genes in 536 Chinese ASD probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Li et al., 2017 identified additional missense variants in the PC gene, and a inherited loss-of-function variant in this gene was observed in an ASD proband from a multiplex family from the iHART cohort (Ruzzo et al., 2019). Functional assessment of the ASD-associated p.Pro1042Arg missense variant in Drosophila using an overexpression-based strategy in Macrogliese et al., 2022 demonstrated that flies overexpressing PC-p.Pro1042Arg exhibited increased lethality when compared with reference protein, indicating a gain-of-function effect.

Molecular Function

This gene encodes pyruvate carboxylase, which requires biotin and ATP to catalyse the carboxylation of pyruvate to oxaloacetate. The active enzyme is a homotetramer arranged in a tetrahedron which is located exclusively in the mitochondrial matrix. Pyruvate carboxylase is involved in gluconeogenesis, lipogenesis, insulin secretion and synthesis of the neurotransmitter glutamate. Biallelic variants in this gene are associated with pyruvate carboxylase deficiency (OMIM 266150); neurological phenotypes associated with this disease include developmental delay, intellectual disability, and seizures.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to PC (8 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
2 Support Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci Sanders SJ , et al. (2015) Yes -
3 Support Genome-wide characteristics of de novo mutations in autism Yuen RK et al. (2016) Yes -
4 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
5 Support Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders Li J , et al. (2017) Yes -
6 Support Genomic Patterns of De Novo Mutation in Simplex Autism Turner TN et al. (2017) Yes -
7 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
8 Recent Recommendation - Marcogliese PC et al. (2022) Yes -
Rare Variants   (17)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.-41917C>T - intron_variant De novo - Simplex 27525107 Yuen RK et al. (2016)
c.309C>G p.Ile103Met missense_variant Unknown - - 28831199 Li J , et al. (2017)
c.562G>A p.Gly188Ser missense_variant Unknown - - 28831199 Li J , et al. (2017)
c.910T>A p.Tyr304Asn missense_variant Unknown - - 28831199 Li J , et al. (2017)
c.1177C>T p.Arg393Cys missense_variant Unknown - - 28831199 Li J , et al. (2017)
c.2173G>T p.Gly725Cys missense_variant Unknown - - 28831199 Li J , et al. (2017)
c.2796A>T p.Glu932Asp missense_variant Unknown - - 28831199 Li J , et al. (2017)
c.-47015C>T - intron_variant De novo - Simplex 28965761 Turner TN et al. (2017)
c.3214G>A p.Gly1072Ser missense_variant Unknown - - 28831199 Li J , et al. (2017)
c.-29403G>A - intron_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.-29677C>T - intron_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.-55121C>T - intron_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.-73743T>A - intron_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.-73757G>A - intron_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.2224-15_2224-14del - intron_variant De novo - - 26402605 Sanders SJ , et al. (2015)
c.3125C>G p.Pro1042Arg missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.3409_3410del p.Leu1137ValfsTer34 frameshift_variant Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

Score Delta: Score remained at 3

criteria met
See SFARI Gene'scoring criteria
3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

4/1/2022
icon
3

Increased from to 3

Krishnan Probability Score

Score 0.48052827581907

Ranking 8035/25841 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 0.71643567007951

Ranking 4396/18225 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 0.90803685386045

Ranking 7275/18665 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 0.15698853360746

Ranking 5030/20870 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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