GGCX

protein-coding

gamma-glutamyl carboxylase

Gene summary

This gene encodes an integral membrane protein of the rough endoplasmic reticulum that carboxylates glutamate residues of vitamin K-dependent proteins to gamma carboxyl glutamate, a modification that is required for their activity. The vitamin K-dependent protein substrates have a propeptide that binds the enzyme, with carbon dioxide, dioxide, and reduced vitamin K acting as co-substrates. Vitamin K-dependent proteins affect a number of physiologic processes including blood coagulation, prevention of vascular calcification, and inflammation. Allelic variants of this gene have been associated with pseudoxanthoma elasticum-like disorder with associated multiple coagulation factor deficiency. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2015]

MANE transcript

NM_000821.7

Inheritance

AR, AD, Digenic

ClinVar variants

P:56U:179B:131

Top phenotype

Vitamin K-dependent clotting factors, combined deficiency of, 1; Pseudoxanthoma elasticum-like disorder with multiple coagulation factor deficiency

gnomAD constraint

pLI —, LoF o/e 0.68

Max pathogenic AF

—

Genomic locus

chr2:85,544,720-85,561,532

External References & Databases

Ensembl (ENSG00000115486)

Transcript & Mutation Effects

hg38 • Region Span ~16.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

body skin hyperlaxity due to vitamin K-dependent coagulation factor deficiencyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0012570

Submitter: Ambry Genetics

pulmonary arterial hypertensionMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0015924

Submitter: ClinGen

*GGCX* was first reported in relation to autosomal dominant pulmonary arterial hypertension (PAH) in 2019 (Zhu et al., PMID: 31727138). 14 variants (9 missense, 4 nonsense, 1 frameshift) reported in 18 probands in 1 publication (PMID:31727138) were included in this curation. The 18 probands were identified using exome sequencing as part of a large cohort (n = 2572 participants) from the National Biological Sample and Data Repository for PAH. The mechanism of pathogenicity was unclear. This gene-disease relationship is also supported by expression evidence (PMID: 23715323). GTEx analysis revealed normal expression in human lung and liver tissue, which is consistent with the PAH phenotype. In summary, the evidence supporting a gene-disease relationship between *GGCX* and autosomal dominant PAH was moderate. This classification was approved by the ClinGen Pulmonary Hypertension GCEP on the meeting date 8/30/2022 (SOP Version 9). The classification was re-evaluated on January 8th, 2025 and May 14th, 2025. As a result of re-evaluation, two missense variants were re-scored as 0 (-0.2) points due to conflicting in silico pathogenicity predictions (two out of three PH GCEP adapted in silico pathogenicity predictor scores not meeting pathogenicity thresholds, i.e. REVEL ≥0.75, CADD >20, AlphaMissense ≥ 0.564). Although a new I/HPAH patient cohort (N=45) from central Taiwan was reported (PMID: 35811711), the variants identified did not pass the PH GCEP pathogenicity threshold for inclusion. The original classification of “moderate” did not change.

body skin hyperlaxity due to vitamin K-dependent coagulation factor deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012570

Submitter: Labcorp Genetics (formerly Invitae)

vitamin K-dependent clotting factors, combined deficiency of, type 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010187

Submitter: Labcorp Genetics (formerly Invitae)

vitamin K-dependent clotting factors, combined deficiency of, type 1SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010187

Submitter: Orphanet

pseudoxanthoma elasticum-like skin manifestations with retinitis pigmentosaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018577

Submitter: Orphanet

body skin hyperlaxity due to vitamin K-dependent coagulation factor deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012570

Submitter: G2P

body skin hyperlaxity due to vitamin K-dependent coagulation factor deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012570

Submitter: Orphanet

vitamin K-dependent clotting factors, combined deficiency of, type 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010187

Submitter: ClinGen

GGCX was first reported in relation to autosomal recessive vitamin K-dependent clotting factors, combined deficiency of, type 1 (VKCFD1) in 1998 (Brenner B, et al., 1998, PMID: 9845520). VKCFD1 is a bleeding disorder characterized by the reduced activities of the procoagulant factors II, VII, IX, and X and anticoagulant proteins C and S. Additional bone, cardiac, skin, and ocular phenotypes are also present in patients. GGCX encodes vitamin K-dependent gamma-carboxylase which catalyzes the carboxylation of specific Glu residues in the intracellular precursors of certain proteins to gamma-carboxyglutamly (Gla) residues in mature proteins. Carboxylation of glutamic acid residues occurs in a number of proteins, including the procoagulants factors II, VII, IX, and X; the anticoagulants protein C and protein S. Carboxylation of other proteins such as osteocalcin and matrix Gla protein may explain additional phenotypes in bone, skin and eyes. For all disease phenotypes the mechanism of pathogenicity is reported to be partial loss of function (hypomorphic). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found overlapping phenotypes with no difference in molecular mechanism or inheritance pattern, therefore, the following disease entities have been lumped into one VKCFD1 disease entity; (OMIM: 277450) Vitamin K-dependent clotting factors, combined deficiency of, 1, and (OMIM: 610842) Pseudoxanthoma elasticum-like disorder with multiple coagulation factor deficiency. Of note a single publication has reported GGCX in relation to Pseudoxanthoma elasticum-like skin manifestations with retinitis pigmentosa (PMID: 24739904), this has not been considered within this curation. As reviewed in PMID: 28125048, at least 32 variants (variant type, e.g. missense, nonsense, frameshift, and splicing) have been reported and 18 variants from 13 probands in 8 publications (PMIDs: 9845520, 17110937, 16720838, 19116367, 26758921, 25151188, 15287948, 29175035) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is also supported by its biochemical function in carboxylation (PMID: 2617472), which is altered in patients (PMID: 19116367), its enriched expression in the liver (PMID: 9166845), and mouse models (PMIDs: 17327402, 24520408). In summary, GGCX is definitively associated with autosomal recessive VKCFD1. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

vitamin K-dependent clotting factors, combined deficiency of, type 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010187

Submitter: Ambry Genetics

vitamin K-dependent clotting factors, combined deficiency of, type 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010187

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Vitamin K-dependent clotting factors, combined deficiency of, 1; Pseudoxanthoma elasticum-like disorder with multiple coagulation factor deficiencyAD/AR/Digenic

Manifestation: Cardiovascular; Dermatologic; Hematologic; Musculoskeletal

Intervention: Cardiovascular; Hematologic

Rationale: 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

Comments: Digenic inheritance (with ABCC6) has been reported in Pseudoxanthoma elasticum

Refs: 5936414; 426915; 7085873; 9845520; 17110937; 18800149; 19116367

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GGCX variants in ClinVar

9 Conditions Cataloged

not providedTotal: 358

Inborn genetic diseasesTotal: 75

Vitamin K-dependent clotting factors, combined deficiency of, type 1Total: 66

GGCX-related disorderTotal: 40

not specifiedTotal: 19

Body skin hyperlaxity due to vitamin K-dependent coagulation factor deficiencyTotal: 19

ThrombocytopeniaTotal: 2

Abnormal bleedingTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000821.7. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			9 clinvar	117 clinvar	2 clinvar	128
missense	11 clinvar	7 clinvar	164 clinvar	12 clinvar		194
nonsense	14 clinvar	4 clinvar				18
start loss						0
frameshift	7 clinvar	4 clinvar	3 clinvar			14
splice donor/acceptor (+/-2bp)	2 clinvar	7 clinvar	3 clinvar			12
Total	34	22	179	129	2	366

Highest pathogenic variant AF is 0.00013137086

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 78 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000821.7	RefSeq	NP_000812.2	15	MANE Select
ENST00000233838.9	Ensembl	ENSP00000233838.3	15	MANE Select
NM_001142269.4	RefSeq	NP_001135741.1	14	Standard
NM_001311312.2	RefSeq	NP_001298241.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Ubiquinone and other terpenoid-quinone biosynthesis - Homo sapiens (human)
Warfarin Pathway, Pharmacodynamics
Aminocaproic Acid Action Pathway
Tranexamic Acid Action Pathway
Urokinase Action Pathway

Biological Process

cellular protein modification process
blood coagulation
peptidyl-glutamic acid carboxylation

Molecular Function

gamma-glutamyl carboxylase activity

Cellular Component

endoplasmic reticulum membrane
membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000233838
Coding exons: 15
Length: 16825
Individuals with no LoFs: 125640
Homozygous LoFs: 0
Heterozygous LoFs: 108
Defined: 125748
p: 0.000430

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.882	357	407	0.877	0.0000245	4908
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00043	0.00043	rare
Latino/Admixed American	0.00046	0.00046	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00092	0.00092	rare
Finnish	0.00023	0.00023	rare
European (Non-Finnish)	0.00044	0.00044	rare
South Asian	0.00033	0.00033	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

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.;

Recessive Scores

pRec: 0.140

Intolerance Scores

LoFtool: 0.0962
RVIS EVS: -0.71
RVIS percentile EVS: 14.78

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.939

Gene Damage Prediction

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