GGCX

gamma-glutamyl carboxylase

Basic information

Region (hg38): 2:85544719-85561532

Links

ENSG00000115486 ∙ NCBI:2677 ∙ OMIM:137167 ∙ HGNC:4247 ∙ Uniprot:P38435 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• body skin hyperlaxity due to vitamin K-dependent coagulation factor deficiency (Moderate), mode of inheritance: AR
• vitamin K-dependent clotting factors, combined deficiency of, type 1 (Strong), mode of inheritance: AR
• body skin hyperlaxity due to vitamin K-dependent coagulation factor deficiency (Supportive), mode of inheritance: AR
• vitamin K-dependent clotting factors, combined deficiency of, type 1 (Supportive), mode of inheritance: AR
• pseudoxanthoma elasticum-like skin manifestations with retinitis pigmentosa (Supportive), mode of inheritance: AR
• body skin hyperlaxity due to vitamin K-dependent coagulation factor deficiency (Strong), mode of inheritance: AR
• vitamin K-dependent clotting factors, combined deficiency of, type 1 (Strong), mode of inheritance: AR
• vitamin K-dependent clotting factors, combined deficiency of, type 1 (Definitive), mode of inheritance: AR
• pulmonary arterial hypertension (Moderate), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Vitamin K-dependent clotting factors, combined deficiency of, 1; Pseudoxanthoma elasticum-like disorder with multiple coagulation factor deficiency	AD/AR/Digenic	Cardiovascular; Hematologic	In Vitamin K-dependent clotting factors, combined deficiency of, 1, vitamin K administration can be effective; In Pseudoxanthoma elasticum-like disorder with multiple coagulation factor deficiency, surveillance and prompt treatment of bleeding diatheses, as well as vascular malformations, may reduce morbidity and mortality	Cardiovascular; Dermatologic; Hematologic; Musculoskeletal	5936414; 426915; 7085873; 9845520; 17110937; 18800149; 19116367
Digenic inheritance (with ABCC6) has been reported in Pseudoxanthoma elasticum

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the GGCX gene.

• not provided (230 variants)
• Vitamin K-dependent clotting factors, combined deficiency of, type 1 (184 variants)
• Vitamin K-Dependent Clotting Factors (20 variants)
• Inborn genetic diseases (16 variants)
• Body skin hyperlaxity due to vitamin K-dependent coagulation factor deficiency (5 variants)
• GGCX-related condition (4 variants)
• Thrombocytopenia;Abnormal bleeding (2 variants)
• Vitamin K-dependent clotting factors, combined deficiency of, type 1;Body skin hyperlaxity due to vitamin K-dependent coagulation factor deficiency (1 variants)
• Body skin hyperlaxity due to vitamin K-dependent coagulation factor deficiency;Vitamin K-dependent clotting factors, combined deficiency of, type 1 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the GGCX gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			9	36	9	54
missense	4	1	102	4	2	113
nonsense	5	1				6
start loss						0
frameshift	4	2	3			9
inframe indel			1			1
splice donor/acceptor (+/-2bp)		1				1
splice region			6	4	1	11
non coding			105	43	45	193
Total	13	5	220	83	56

Highest pathogenic variant AF is 0.0000394

Variants in GGCX

This is a list of pathogenic ClinVar variants found in the GGCX region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
2-85544937-GA-G		Vitamin K-Dependent Clotting Factors	Uncertain significance (Jun 14, 2016)
2-85544938-A-AT		Vitamin K-Dependent Clotting Factors	Uncertain significance (Jun 14, 2016)
2-85545039-A-T		Vitamin K-dependent clotting factors, combined deficiency of, type 1	Uncertain significance (Jan 13, 2018)
2-85545086-G-A		Vitamin K-dependent clotting factors, combined deficiency of, type 1	Uncertain significance (Jan 13, 2018)
2-85545094-A-G		Vitamin K-dependent clotting factors, combined deficiency of, type 1	Benign (Apr 27, 2017)
2-85545136-C-T		Vitamin K-dependent clotting factors, combined deficiency of, type 1	Uncertain significance (Jan 13, 2018)
2-85545190-G-A		Vitamin K-dependent clotting factors, combined deficiency of, type 1	Uncertain significance (Jan 13, 2018)
2-85545208-T-G		Vitamin K-dependent clotting factors, combined deficiency of, type 1	Likely benign (Jan 13, 2018)
2-85545214-C-T		Vitamin K-dependent clotting factors, combined deficiency of, type 1	Uncertain significance (Jan 13, 2018)
2-85545253-C-T		Vitamin K-dependent clotting factors, combined deficiency of, type 1	Uncertain significance (Jan 13, 2018)
2-85545355-C-T		Vitamin K-dependent clotting factors, combined deficiency of, type 1	Benign (Jan 13, 2018)
2-85545372-C-T		Vitamin K-dependent clotting factors, combined deficiency of, type 1	Uncertain significance (Jan 13, 2018)
2-85545396-T-C		Vitamin K-Dependent Clotting Factors	Uncertain significance (Jun 14, 2016)
2-85545425-C-T		Vitamin K-dependent clotting factors, combined deficiency of, type 1	Benign (Jan 12, 2018)
2-85545459-A-G		Vitamin K-dependent clotting factors, combined deficiency of, type 1	Uncertain significance (Jan 12, 2018)
2-85545505-C-T		Vitamin K-dependent clotting factors, combined deficiency of, type 1	Benign (Jan 13, 2018)
2-85545521-A-G		Vitamin K-dependent clotting factors, combined deficiency of, type 1	Uncertain significance (Jan 12, 2018)
2-85545537-C-T		Vitamin K-dependent clotting factors, combined deficiency of, type 1	Uncertain significance (Jan 13, 2018)
2-85545568-G-A		Vitamin K-dependent clotting factors, combined deficiency of, type 1	Uncertain significance (Jan 13, 2018)
2-85545620-A-G		Vitamin K-dependent clotting factors, combined deficiency of, type 1	Likely benign (Jan 13, 2018)
2-85545646-C-G		Vitamin K-dependent clotting factors, combined deficiency of, type 1	Uncertain significance (Jan 12, 2018)
2-85545692-G-C		Vitamin K-dependent clotting factors, combined deficiency of, type 1	Uncertain significance (Jan 13, 2018)
2-85545719-C-T		Vitamin K-dependent clotting factors, combined deficiency of, type 1	Uncertain significance (Jan 12, 2018)
2-85545739-A-C		Vitamin K-dependent clotting factors, combined deficiency of, type 1	Uncertain significance (Jan 15, 2018)
2-85545856-C-T		Vitamin K-dependent clotting factors, combined deficiency of, type 1	Uncertain significance (Jan 12, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
GGCX	protein_coding	protein_coding	ENST00000233838	15	16825

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
2.02e-14	0.806	125640	0	108	125748	0.000430

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.882	357	407	0.877	0.0000245	4908
Missense in Polyphen		136	163.82	0.83017		1970
Synonymous	-0.824	174	161	1.08	0.00000827	1531
Loss of Function	1.91	28	41.3	0.678	0.00000243	439

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000894	0.000893
Ashkenazi Jewish	0.000199	0.000198
East Asian	0.000925	0.000925
Finnish	0.000232	0.000231
European (Non-Finnish)	0.000442	0.000440
Middle Eastern	0.000925	0.000925
South Asian	0.000327	0.000327
Other	0.000164	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Mediates the vitamin K-dependent carboxylation of glutamate residues to calcium-binding gamma-carboxyglutamate (Gla) residues with the concomitant conversion of the reduced hydroquinone form of vitamin K to vitamin K epoxide. {ECO:0000269|PubMed:17073445}.
• Disease: DISEASE: Combined deficiency of vitamin K-dependent clotting factors 1 (VKCFD1) [MIM:277450]: VKCFD leads to a bleeding tendency that is usually reversed by oral administration of vitamin K. {ECO:0000269|PubMed:10934213, ECO:0000269|PubMed:11071668, ECO:0000269|PubMed:15287948, ECO:0000269|PubMed:9845520}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Pseudoxanthoma elasticum-like disorder with multiple coagulation factor deficiency (PXEL-MCFD) [MIM:610842]: Characterized by hyperlaxity of the skin involving the entire body. Important phenotypic differences with classical PXE include much more severe skin laxity with spreading toward the trunk and limbs with thick, leathery skin folds rather than confinement to flexural areas, and no decrease in visual acuity. Moreover, detailed electron microscopic analyzes revealed that alterations of elastic fibers as well as their mineralization are slightly different from those in classic PXE. {ECO:0000269|PubMed:17110937}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Ubiquinone and other terpenoid-quinone biosynthesis - Homo sapiens (human);Warfarin Pathway, Pharmacodynamics;Aminocaproic Acid Action Pathway;Tranexamic Acid Action Pathway;Urokinase Action Pathway;Reteplase Action Pathway;Streptokinase Action Pathway;Tenecteplase Action Pathway;Alteplase Action Pathway;Anistreplase Action Pathway;Aprotinin Action Pathway;Phenindione Action Pathway;Dicoumarol Action Pathway;Warfarin Action Pathway;Acenocoumarol Action Pathway;Vitamin K Metabolism;Coagulation ;Bivalirudin Action Pathway;Argatroban Action Pathway;Ardeparin Action Pathway;Heparin Action Pathway;Fondaparinux Action Pathway;Enoxaparin Action Pathway;Phenprocoumon Action Pathway;Dicumarol Action Pathway;Ximelagatran Action Pathway;Lepirudin Action Pathway;Post-translational protein modification;Metabolism of proteins;Gamma-carboxylation of protein precursors;Gamma-carboxylation, transport, and amino-terminal cleavage of proteins;Gamma carboxylation, hypusine formation and arylsulfatase activation (Consensus)

Recessive Scores

• pRec: 0.140

Intolerance Scores

• loftool: 0.0962
• rvis_EVS: -0.71
• rvis_percentile_EVS: 14.78

Haploinsufficiency Scores

• pHI: 0.142
• hipred: Y
• hipred_score: 0.526
• ghis: 0.511

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.939

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Ggcx
• Phenotype: growth/size/body region phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); homeostasis/metabolism phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); reproductive system phenotype; hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan)

Gene ontology

• Biological process: cellular protein modification process;blood coagulation;peptidyl-glutamic acid carboxylation
• Cellular component: endoplasmic reticulum membrane;membrane;integral component of membrane
• Molecular function: gamma-glutamyl carboxylase activity