PC (pyruvate carboxylase)

Gene

• Entrez ID: 5091
• Gene name: Pyruvate carboxylase
• Gene symbol: PC
• Synonyms (NCBI Gene): PCB
• Chromosome: 11
• Chromosome location: 11q13.2
• Summary: 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. Pyruva

SNPs

SNP ID	Visualize variation	Clinical significance	Consequence
rs2229745	G>A	Benign, conflicting-interpretations-of-pathogenicity	Synonymous variant, coding sequence variant
rs28940589	C>T	Pathogenic	Coding sequence variant, missense variant
rs28940590	C>A	Pathogenic	Coding sequence variant, missense variant
rs28940591	A>C,G	Pathogenic	Coding sequence variant, missense variant, genic upstream transcript variant
rs113994141	G>A	Pathogenic	Genic upstream transcript variant, coding sequence variant, missense variant
rs113994142	A>C,G,T	Uncertain-significance, pathogenic, likely-pathogenic	Genic upstream transcript variant, coding sequence variant, missense variant
rs113994143	G>A	Pathogenic	Genic upstream transcript variant, coding sequence variant, missense variant
rs113994144	T>C,G	Pathogenic	Missense variant, coding sequence variant
rs113994145	C>T	Pathogenic, pathogenic-likely-pathogenic	Missense variant, coding sequence variant
rs113994146	G>T	Pathogenic	Coding sequence variant, stop gained
rs113994147	G>A	Pathogenic	Missense variant, coding sequence variant
rs113994148	AG>-	Pathogenic	Frameshift variant, coding sequence variant
rs119103242	C>A,T	Pathogenic	Coding sequence variant, missense variant
rs144583275	G>A,T	Likely-pathogenic, benign, uncertain-significance	Coding sequence variant, stop gained, genic upstream transcript variant, synonymous variant
rs200030109	C>A	Uncertain-significance, likely-pathogenic	Coding sequence variant, missense variant, genic upstream transcript variant
rs568925019	C>T	Likely-pathogenic	Coding sequence variant, missense variant
rs748620956	GCCC>-	Uncertain-significance, conflicting-interpretations-of-pathogenicity	Intron variant, genic upstream transcript variant
rs755640269	C>A,T	Likely-pathogenic	Splice donor variant, genic upstream transcript variant
rs756355930	AC>-	Pathogenic	Coding sequence variant, frameshift variant
rs760108147	C>A,T	Likely-pathogenic	Missense variant, coding sequence variant
rs763433647	A>G	Likely-pathogenic	Splice donor variant, genic upstream transcript variant
rs768514713	G>A,C	Pathogenic	Coding sequence variant, stop gained, genic upstream transcript variant, missense variant
rs769177104	C>T	Likely-pathogenic, conflicting-interpretations-of-pathogenicity	Coding sequence variant, genic upstream transcript variant, missense variant
rs796052029	C>T	Likely-pathogenic	Missense variant, coding sequence variant
rs796052030	G>A,T	Pathogenic	Missense variant, coding sequence variant, genic upstream transcript variant
rs796052032	G>A	Uncertain-significance, likely-pathogenic	Missense variant, coding sequence variant
rs928225163	G>A,C	Pathogenic	Genic upstream transcript variant, coding sequence variant, missense variant
rs1057520687	A>G	Uncertain-significance, likely-pathogenic	Genic upstream transcript variant, coding sequence variant, missense variant
rs1057524862	C>T	Likely-pathogenic	Genic upstream transcript variant, coding sequence variant, missense variant
rs1064796030	T>-	Likely-pathogenic	Genic upstream transcript variant, coding sequence variant, frameshift variant
rs1555013840	->ATCA	Likely-pathogenic	Coding sequence variant, frameshift variant
rs1555014332	AC>T	Likely-pathogenic	Coding sequence variant, frameshift variant
rs1555014957	C>A	Pathogenic	Coding sequence variant, missense variant
rs1555025823	C>T	Likely-pathogenic	Splice donor variant, genic upstream transcript variant
rs1565209327	->A	Pathogenic	Coding sequence variant, frameshift variant
rs1565245427	GCTC>-	Pathogenic	Coding sequence variant, frameshift variant, genic upstream transcript variant
rs1591117575	T>A	Pathogenic	Coding sequence variant, missense variant
rs1591186383	T>C	Likely-pathogenic	Genic upstream transcript variant, coding sequence variant, missense variant

miRNA

miRTarBase ID	miRNA	Experiments	Reference
MIRT017539	hsa-miR-335-5p	Microarray	18185580
MIRT045724	hsa-miR-125a-5p	CLASH	23622248
MIRT1216229	hsa-miR-1909	CLIP-seq
MIRT1216230	hsa-miR-3153	CLIP-seq
MIRT2062453	hsa-miR-1538	CLIP-seq
MIRT2062454	hsa-miR-3667-3p	CLIP-seq
MIRT2062455	hsa-miR-4297	CLIP-seq
MIRT2062456	hsa-miR-4745-3p	CLIP-seq
MIRT2290881	hsa-miR-31	CLIP-seq

Transcription factors

Transcription factor	Regulation	Reference
AR	Activation	18497079
MAFA	Activation	17149590

Gene ontology (GO)

GO ID	Ontology	Definition	Evidence	Reference
GO:0000166	Function	Nucleotide binding	IEA
GO:0003824	Function	Catalytic activity	IEA
GO:0004736	Function	Pyruvate carboxylase activity	EXP	12437512
GO:0004736	Function	Pyruvate carboxylase activity	IBA
GO:0004736	Function	Pyruvate carboxylase activity	IEA
GO:0004736	Function	Pyruvate carboxylase activity	IMP	9585002
GO:0004736	Function	Pyruvate carboxylase activity	TAS	7918683
GO:0005515	Function	Protein binding	IPI	23861867, 34547241
GO:0005524	Function	ATP binding	IEA
GO:0005524	Function	ATP binding	TAS	8048912
GO:0005737	Component	Cytoplasm	IDA	23861867, 34547241
GO:0005739	Component	Mitochondrion	HTP	34800366
GO:0005739	Component	Mitochondrion	IBA
GO:0005739	Component	Mitochondrion	IDA	16729965
GO:0005739	Component	Mitochondrion	IEA
GO:0005759	Component	Mitochondrial matrix	IEA
GO:0005759	Component	Mitochondrial matrix	TAS
GO:0005829	Component	Cytosol	IDA
GO:0005829	Component	Cytosol	IEA
GO:0005829	Component	Cytosol	TAS
GO:0006094	Process	Gluconeogenesis	IBA
GO:0006094	Process	Gluconeogenesis	IEA
GO:0006094	Process	Gluconeogenesis	TAS
GO:0006629	Process	Lipid metabolic process	IEA
GO:0006739	Process	NADP+ metabolic process	IDA	34547241
GO:0009374	Function	Biotin binding	IEA
GO:0009374	Function	Biotin binding	TAS	8048912
GO:0010629	Process	Negative regulation of gene expression	IMP	23861867
GO:0016874	Function	Ligase activity	IEA
GO:0019074	Process	Viral RNA genome packaging	IMP	23861867
GO:0019076	Process	Viral release from host cell	IMP	23861867
GO:0019674	Process	NAD+ metabolic process	IDA	34547241
GO:0042802	Function	Identical protein binding	IPI	18297087, 34547241
GO:0044281	Process	Small molecule metabolic process	IEA
GO:0044794	Process	Host-mediated activation of viral process	IMP	23861867
GO:0046872	Function	Metal ion binding	IEA

Other IDs

• MIM: 608786
• HGNC: 8636
• e!Ensembl: ENSG00000173599

Protein

• UniProt ID: P11498
• Protein name: Pyruvate carboxylase, mitochondrial (EC 6.4.1.1) (Pyruvic carboxylase) (PCB)
• Protein function: Pyruvate carboxylase catalyzes a 2-step reaction, involving the ATP-dependent carboxylation of the covalently attached biotin in the first step and the transfer of the carboxyl group to pyruvate in the second. Catalyzes in a tissue specific mann
• PDB: 3BG3, 3BG9, 7WTA, 7WTB, 7WTC, 7WTD, 7WTE, 8HWL, 8J7O, 8XL9
• Family and domains:

  Pfam

  Accession	ID	Position in sequence	Description	Type
  PF00289	Biotin_carb_N	36 → 146	Biotin carboxylase, N-terminal domain	Domain
  PF02786	CPSase_L_D2	151 → 360	Carbamoyl-phosphate synthase L chain, ATP binding domain	Domain
  PF02785	Biotin_carb_C	375 → 483	Biotin carboxylase C-terminal domain	Domain
  PF00682	HMGL-like	563 → 837	HMGL-like	Domain
  PF02436	PYC_OADA	861 → 1061	Conserved carboxylase domain	Domain
  PF00364	Biotin_lipoyl	1110 → 1177	Biotin-requiring enzyme	Domain

• Sequence:

  MLKFRTVHGGLRLLGIRRTSTAPAASPNVRRLEYKPIKKVMVANRGEIAIRVFRACTELG
  IRTVAIYSEQDTGQMHRQKADEAYLIGRGLAPVQAYLHIPDIIKVAKENNVDAVHPGYGF
  LSERADFAQACQDAGVRFIGPSPEVVRKMGDKVEARAIAIAAGVPVVPGTDAPITSLHEA
  HEFSNTYGFPIIFKAAYGGGGRGMRVVHSYEELEENYTRAYSEALAAFGNGALFVEKFIE
  KPRHIEVQILGDQYGNILHLYERDCSIQRRHQKVVEIAPAAHLDPQLRTRLTSDSVKLAK
  QVGYENAGTVEFLVDRHGKHYFIEVNSRLQVEHTVTEEITDVDLVHAQIHVAEGRSLPDL
  GLRQENIRINGCAIQCRVTTEDPARSFQPDTGRIEVFRSGEGMGIRLDNASAFQGAVISP
  HYDSLLVKVIAHGKDHPTAATKMSRALAEFRVRGVKTNIAFLQNVLNNQQFLAGTVDTQF
  IDENPELFQLRPAQNRAQKLLHYLGHVMVNGPTTPIPVKASPSPTDPVVPAVPIGPPPAG
  FRDILLREGPEGFARAVRNHPGLLLMDTTFRDAHQSLLATRVRTHDLKKIAPYVAHNFSK
  LFSMENWGGATFDVAMRFLYECPWRRLQELRELIPNIPFQMLLRGANAVGYTNYPDNVVF
  KFCEVAKENGMDVFRVFDSLNYLPNMLLGMEAAGSAGGVVEAAISYTGDVADPSRTKYSL
  QYYMGLAEELVRAGTHILCIKDMAGLLKPTACTMLVSSLRDRFPDLPLHIHTHDTSGAGV
  AAMLACAQAGADVVDVAADSMSGMTSQPSMGALVACTRGTPLDTEVPMERVFDYSEYWEG
  ARGLYAAFDCTATMKSGNSDVYENEIPGGQYTNLHFQAHSMGLGSKFKEVKKAYVEANQM
  LGDLIKVTPSSKIVGDLAQFMVQNGLSRAEAEAQAEELSFPRSVVEFLQGYIGVPHGGFP
  EPFRSKVLKDLPRVEGRPGASLPPLDLQALEKELVDRHGEEVTPEDVLSAAMYPDVFAHF
  KDFTATFGPLDSLNTRLFLQGPKIAEEFEVELERGKTLHIKALAVSDLNRAGQRQVFFEL
  NGQLRSILVKDTQAMKEMHFHPKALKDVKGQIGAPMPGKVIDIKVVAGAKVAKGQPLCVL
  SAMKMETVVTSPMEGTVRKVHVTKDMTLEGDDLILEIE

• Sequence length: 1178

Pathways

KEGG:

Citrate cycle (TCA cycle)
Pyruvate metabolism
Metabolic pathways
Carbon metabolism
Biosynthesis of amino acids

Reactome:

Biotin transport and metabolism
Defective HLCS causes multiple carboxylase deficiency
Gluconeogenesis

Associated diseases

Evidence Score:

• ★☆☆☆☆  Gene-disease association found in Text Mining only
• ★★☆☆☆  Found in Text Mining and Unknown/Other Associations
• ★★★☆☆  Reported in Unknown/Other Associations across ≥2 Sources
• ★★★★☆  ClinVar: Pathogenic/Likely Pathogenic (<5 Variants)
• ★★★★★  ClinVar: Pathogenic/Likely Pathogenic (≥5 Variants)

Causal
Phenotype Name	Clinical Significance	dbSNP ID	RCV Accession	Evidence Score
Congenital lactic acidosis	Pathogenic	rs1591117575	RCV001003597	★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)
Global developmental delay	Pathogenic	rs1407756066	RCV001255416	★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)
Pyruvate carboxylase deficiency	Pathogenic; Likely pathogenic	rs1230803568, rs2135822173, rs2135785399, rs2135789146, rs2135790424, rs2135795582, rs2135800153, rs2135803326, rs766242199, rs2135917452, rs1482845179, rs2135822119, rs2135805611, rs1555015018, rs2135798857, rs2135904801, rs112948607, rs2135814786, rs2135903791, rs2135917561, rs2135786512, rs755640269, rs2135788673, rs1487446205, rs2135917031, rs2135785388, rs2135791416, rs2135940752, rs2135783409, rs1310884700, rs2135917229, rs2135941937, rs2135786710, rs2135940951, rs2135809396, rs1304770743, rs1358651584, rs1358550062, rs2495743452, rs28940589, rs28940590, rs28940591, rs113994143, rs2135813862, rs119103242, rs1565209327, rs2495453717, rs2495486867, rs2495437841, rs2495781557, rs867332885, rs1169371609, rs2495450786, rs2495673466, rs2495443430, rs2495773871, rs1356000803, rs2495421429, rs2495765339, rs748009590, rs2495494945, rs2495440025, rs2495761226, rs2495806084, rs2495799331, rs2495774531, rs2495496525, rs2495496267, rs2495494399, rs2495495266, rs2495494758, rs2495440377, rs2495799854, rs2495425632, rs2495805436, rs2495791165, rs2495797373, rs2495414125, rs2495496043, rs2495406056, rs2495790661, rs2495798589, rs2495490951, rs2495798799, rs1415973565, rs2495404851, rs770383752, rs147066473, rs796052032, rs2495444900, rs2495436147, rs2495508261, rs776114073, rs2495672932, rs2495428020, rs2495796917, rs1946727506, rs534635326, rs946554235, rs2495468895, rs2531803201, rs1945380233, rs2495411828, rs2495474689, rs2495457094, rs2495401265, rs2495801113, rs1486094843, rs2495399241, rs2495485309, rs2495380515, rs2495790186, rs2495382261, rs2495410373, rs2495391310, rs2495378431, rs755082537, rs2495406855, rs2495804812, rs2495400851, rs2495399570, rs2495781450, rs2495416125, rs2495456777, rs2495400122, rs2495509213, rs2495762440, rs2495672743, rs2495487509, rs1196710763, rs2495449986, rs1018564264, rs2495800352, rs2495485616, rs2495388599, rs113994145, rs113994146, rs113994148, rs2495421234, rs119103241, rs768514713, rs1555014957, rs1555014332, rs756355930, rs1555013840, rs1555025823, rs144583275, rs763433647, rs1436643226, rs1565245427, rs1565214970, rs1591186383, rs1324931037, rs1946484568, rs1945585636, rs1946669738, rs1946724126, rs1945617407	RCV001332612 RCV001377234 RCV001388927 RCV001384114 RCV001380678 RCV001383937 RCV001380178 RCV001390025 RCV001383248 RCV001386564 RCV001542480 RCV001774754 RCV001774756 RCV001774758 RCV001774759 RCV001784799 RCV001782570 RCV001899258 RCV001928241 RCV001941742 RCV001904462 RCV001995264 RCV002043993 RCV001921439 RCV001944424 RCV001927018 RCV001995696 RCV001939586 RCV001951184 RCV001951152 RCV001956371 RCV001949368 RCV001914904 RCV002048351 RCV001935982 RCV001983485 RCV002249120 RCV002254835 RCV002283739 RCV000002175 RCV000002176 RCV000002177 RCV000002178 RCV000002179 RCV000002182 RCV000002183 RCV002309599 RCV002309615 RCV002309686 RCV002309823 RCV002309929 RCV002309992 RCV002308015 RCV002308040 RCV002308128 RCV002308135 RCV002308186 RCV002308190 RCV002309018 RCV002309072 RCV002309117 RCV002309177 RCV002309192 RCV002309310 RCV002309380 RCV002309426 RCV002309464 RCV002309475 RCV002309477 RCV002309491 RCV002309505 RCV002306881 RCV002306917 RCV002306920 RCV002307025 RCV002307089 RCV002307240 RCV002307323 RCV002310177 RCV002310201 RCV002310415 RCV002310473 RCV002310562 RCV002308441 RCV003062414 RCV003087326 RCV003120052 RCV002630229 RCV002630811 RCV000675135 RCV002861433 RCV003011114 RCV003005068 RCV002999782 RCV003020020 RCV003476618 RCV003476619 RCV003476620 RCV003476621 RCV003476622 RCV003476623 RCV003476624 RCV003476625 RCV003476626 RCV003476627 RCV003476628 RCV003476629 RCV003476630 RCV003476631 RCV003476632 RCV003476633 RCV003498807 RCV003498199 RCV003498883 RCV003499655 RCV003500002 RCV003497388 RCV003499975 RCV003498548 RCV003498333 RCV003499503 RCV003604047 RCV003604248 RCV003604316 RCV003604611 RCV003604626 RCV003604954 RCV003605045 RCV003866362 RCV004574439 RCV004574440 RCV004574441 RCV004574442 RCV004574443 RCV004574444 RCV004574445 RCV000020384 RCV003811121 RCV000020391 RCV004586455 RCV004586456 RCV000504155 RCV000516896 RCV000576201 RCV000670716 RCV000670028 RCV000672343 RCV000670832 RCV000672699 RCV000669751 RCV000666561 RCV000667975 RCV000698019 RCV000779075 RCV000988582 RCV001196289 RCV001222498 RCV001208930 RCV001214966 RCV001254095 RCV001261600	★★★★★ ClinVar: Pathogenic / Likely Pathogenic (≥5 Variants)
Thrombophilia due to protein C deficiency, autosomal dominant	Likely pathogenic; Pathogenic	rs766242199	RCV005912635	★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)
Thrombophilia due to protein C deficiency, autosomal recessive	Likely pathogenic; Pathogenic	rs766242199	RCV005912635	★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)

Unknown / Other Associations
Phenotype Name	Clinical Significance	Source	Evidence Score
Acute myeloid leukemia	Benign; Conflicting classifications of pathogenicity	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
BIPOLAR DISORDER	—	CTD, Disgenet, GWAS catalog CTD, Disgenet, GWAS catalog CTD, Disgenet, GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
BIPOLAR I DISORDER	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
BIPOLAR I DISORDER, MOST RECENT EPISODE MANIC	—	Disgenet	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
BREAST CANCER	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
BURKITT LYMPHOMA	—	CTD	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Cervical cancer	Uncertain significance; Benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Cholangiocarcinoma	Conflicting classifications of pathogenicity	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Clear cell carcinoma of kidney	Conflicting classifications of pathogenicity	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
DEPRESSION, BIPOLAR	—	Disgenet	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
DIABETES MELLITUS, NON-INSULIN-DEPENDENT	—	Disgenet	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
ESTROGEN-RECEPTOR POSITIVE BREAST CANCER	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Gastric cancer	Benign; Likely benign; Uncertain significance	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
GOUT	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Hepatocellular carcinoma	Benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
INSOMNIA	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
LIVER CIRRHOSIS, EXPERIMENTAL	—	CTD	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Malignant tumor of esophagus	Benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Malignant tumor of urinary bladder	Conflicting classifications of pathogenicity	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
MIXED BIPOLAR I DISORDER	—	Disgenet	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Nonpapillary renal cell carcinoma	Conflicting classifications of pathogenicity	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Ovarian serous cystadenocarcinoma	Conflicting classifications of pathogenicity	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
PC-related disorder	Likely benign; Benign; Conflicting classifications of pathogenicity	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Sarcoma	Benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
SQUAMOUS CELL LUNG CARCINOMA	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Thymoma	Benign; Uncertain significance	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Thyroid cancer, nonmedullary, 1	Conflicting classifications of pathogenicity	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Uterine carcinosarcoma	Benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Uterine corpus endometrial carcinoma	Benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Uveal melanoma	Benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations