Hypercoagulability syndrome due to glycosylphosphatidylinositol deficiency

Summary

Hypercoagulability syndrome due to glycosylphosphatidylinositol deficiency (MONDO:0012465) is a disease with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 3
• ClinVar variants: 103

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	hypercoagulability syndrome due to glycosylphosphatidylinositol deficiency
Mondo ID	MONDO:0012465
OMIM	610293
Orphanet	83639
ICD-11	1811042875
SNOMED CT	724344004
UMLS	C5201145
MedGen	1684821
GARD	0009965
Is cancer (heuristic)	no

Also known as: congenital disorder of glycosylation due to PIGM deficiency · GPID · PIGM-CDG

Data availability: 103 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › hematologic disorder › congenital hematological disorder › hypercoagulability syndrome due to glycosylphosphatidylinositol deficiency

Related subtypes (20): congenital anemia, congenital agammaglobulinemia, sulfhemoglobinemia, congenital, congenital factor XII deficiency, leukocyte adhesion deficiency type II, thrombocytopenia-absent radius syndrome, congenital thrombotic thrombocytopenic purpura, radio-ulnar synostosis-amegakaryocytic thrombocytopenia syndrome, GNE myopathy, congenital factor XI deficiency, congenital plasminogen activator inhibitor type 1 deficiency, congenital analbuminemia, macrothrombocytopenia-lymphedema-developmental delay-facial dysmorphism-camptodactyly syndrome, constitutional neutropenia, congenital vitamin K-dependent coagulation factors deficiency, congenital secondary polycythemia, hereditary thrombocytosis with transverse limb defect, congenital factor XIII deficiency, congenital progressive bone marrow failure-B-cell immunodeficiency-skeletal dysplasia syndrome, congenital amegakaryocytic thrombocytopenia 1

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

103 retrieved; paginated sample, class counts are floors:

79 uncertain significance, 10 likely benign, 6 benign, 3 benign/likely benign, 2 conflicting classifications of pathogenicity, 1 no classifications from unflagged records, 1 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3362856	NM_145167.3(PIGM):c.401del (p.Asn134fs)	PIGM	Pathogenic	criteria provided, single submitter
520658	NM_145167.3(PIGM):c.2T>C (p.Met1Thr)	PIGM	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2582401	NM_145167.3(PIGM):c.538A>T (p.Lys180Ter)	PIGM	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2639491	NM_145167.3(PIGM):c.756A>G (p.Glu252=)	PIGM	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
634642	NM_001346754.2(PIGW):c.608T>G (p.Leu203Trp)	MYO19	Uncertain significance	criteria provided, single submitter
1004738	NM_145167.3(PIGM):c.59G>A (p.Gly20Asp)	PIGM	Uncertain significance	criteria provided, multiple submitters, no conflicts
1020292	NM_145167.3(PIGM):c.1042C>G (p.Pro348Ala)	PIGM	Uncertain significance	criteria provided, multiple submitters, no conflicts
1023331	NM_145167.3(PIGM):c.412A>G (p.Met138Val)	PIGM	Uncertain significance	criteria provided, multiple submitters, no conflicts
1055901	NM_145167.3(PIGM):c.1001A>C (p.Gln334Pro)	PIGM	Uncertain significance	criteria provided, multiple submitters, no conflicts
1288	NC_000001.11:g.160032009G>C	PIGM	no classifications from unflagged records	no classifications from unflagged records
1394697	NM_145167.3(PIGM):c.292C>A (p.Leu98Ile)	PIGM	Uncertain significance	criteria provided, single submitter
1398285	NM_145167.3(PIGM):c.649G>A (p.Glu217Lys)	PIGM	Uncertain significance	criteria provided, single submitter
1424323	NM_145167.3(PIGM):c.1199A>G (p.Asn400Ser)	PIGM	Uncertain significance	criteria provided, single submitter
1438684	NM_145167.3(PIGM):c.404C>T (p.Pro135Leu)	PIGM	Uncertain significance	criteria provided, multiple submitters, no conflicts
1478126	NM_145167.3(PIGM):c.230C>T (p.Thr77Ile)	PIGM	Uncertain significance	criteria provided, multiple submitters, no conflicts
1716499	NM_145167.3(PIGM):c.1217A>C (p.Gln406Pro)	PIGM	Uncertain significance	criteria provided, single submitter
1719666	NM_145167.3(PIGM):c.686T>C (p.Leu229Pro)	PIGM	Uncertain significance	criteria provided, single submitter
1916848	NM_145167.3(PIGM):c.1093T>G (p.Phe365Val)	PIGM	Uncertain significance	criteria provided, single submitter
193497	NM_145167.3(PIGM):c.137G>A (p.Arg46Lys)	PIGM	Uncertain significance	criteria provided, multiple submitters, no conflicts
1959200	NM_145167.3(PIGM):c.364C>T (p.Arg122Cys)	PIGM	Uncertain significance	criteria provided, single submitter
1967671	NM_145167.3(PIGM):c.114C>G (p.Phe38Leu)	PIGM	Uncertain significance	criteria provided, single submitter
1973487	NM_145167.3(PIGM):c.1100G>T (p.Gly367Val)	PIGM	Uncertain significance	criteria provided, single submitter
1982390	NM_145167.3(PIGM):c.538A>G (p.Lys180Glu)	PIGM	Uncertain significance	criteria provided, multiple submitters, no conflicts
1985579	NM_145167.3(PIGM):c.608G>A (p.Ser203Asn)	PIGM	Uncertain significance	criteria provided, single submitter
2059769	NM_145167.3(PIGM):c.518A>G (p.Tyr173Cys)	PIGM	Uncertain significance	criteria provided, multiple submitters, no conflicts
2063350	NM_145167.3(PIGM):c.232C>T (p.Pro78Ser)	PIGM	Uncertain significance	criteria provided, multiple submitters, no conflicts
2071768	NM_145167.3(PIGM):c.1090T>C (p.Trp364Arg)	PIGM	Uncertain significance	criteria provided, multiple submitters, no conflicts
2081907	NM_145167.3(PIGM):c.130C>T (p.His44Tyr)	PIGM	Uncertain significance	criteria provided, multiple submitters, no conflicts
2103956	NM_145167.3(PIGM):c.805C>T (p.His269Tyr)	PIGM	Uncertain significance	criteria provided, single submitter
2142785	NM_145167.3(PIGM):c.613C>T (p.Arg205Cys)	PIGM	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
PIGM	Moderate	Autosomal recessive	hypercoagulability syndrome due to glycosylphosphatidylinositol deficiency	5
PIGW	Supportive	Autosomal recessive	hypercoagulability syndrome due to glycosylphosphatidylinositol deficiency	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PIGM	Orphanet:83639	Hypercoagulability syndrome due to glycosylphosphatidylinositol deficiency
PIGW	Orphanet:247262	Hyperphosphatasia-intellectual disability syndrome
PIGW	Orphanet:83639	Hypercoagulability syndrome due to glycosylphosphatidylinositol deficiency

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PIGM	HGNC:18858	ENSG00000143315	Q9H3S5	GPI alpha-1,4-mannosyltransferase I, catalytic subunit	gencc,clinvar
PIGW	HGNC:23213	ENSG00000277161	Q7Z7B1	Glucosaminyl-phosphatidylinositol-acyltransferase PIGW	gencc
MYO19	HGNC:26234	ENSG00000278259	Q96H55	Unconventional myosin-XIX	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PIGM	GPI alpha-1,4-mannosyltransferase I, catalytic subunit	Catalytic subunit of the glycosylphosphatidylinositol-mannosyltransferase I complex which catalyzes the transfer of the first mannose, via an alpha-1,4 bond from a dolichol-phosphate-mannose (Dol-P-Man) to a 2-acyl-6-alpha-D-glucosaminyl-1…
PIGW	Glucosaminyl-phosphatidylinositol-acyltransferase PIGW	Acyltransferase that catalyzes the acyl transfer from an acyl-CoA at the 2-OH position of the inositol ring of a 6-(alpha-D-glucosaminyl)-1-(1,2-diacyl-sn-glycero-3-phospho)-1D-myo-inositol (glucosaminyl phosphatidylinositol, GlcN-PI) to g…
MYO19	Unconventional myosin-XIX	Actin-based motor molecule with ATPase activity that localizes to the mitochondrion outer membrane.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PIGM	Other/Unknown	no		PIG-M
PIGW	Other/Unknown	no		PIGW/GWT1
MYO19	Other/Unknown	no		Myosin_head_motor_dom-like, P-loop_NTPase, MYSc_Myo19

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ileal mucosa	1
inferior vagus X ganglion	1
subthalamic nucleus	1
endometrium	1
gastrocnemius	1
islet of Langerhans	1
metanephros cortex	1
skin of abdomen	1
skin of leg	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PIGM	235	ubiquitous	marker	ileal mucosa, subthalamic nucleus, inferior vagus X ganglion
PIGW	134	ubiquitous	yes	islet of Langerhans, endometrium, gastrocnemius
MYO19	244	ubiquitous	yes	skin of leg, skin of abdomen, metanephros cortex

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MYO19	3,000
PIGW	1,715
PIGM	838

Intra-cohort edges

A	B	Sources
MYO19	PIGW	string_interaction
PIGM	PIGW	string_interaction

Structural data

PDB: 0 · AlphaFold-only: 3 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PIGM	Q9H3S5	90.10
PIGW	Q7Z7B1	87.17
MYO19	Q96H55	76.93

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 3 evidence-associated genes (3 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Synthesis of glycosylphosphatidylinositol (GPI)	2	423.0×	4e-05	PIGM, PIGW
RHOT1 GTPase cycle	1	761.3×	0.003	MYO19
Miro GTPase Cycle	1	761.3×	0.003	MYO19
RHOT2 GTPase cycle	1	543.8×	0.003	MYO19
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	11.2×	0.104	MYO19
Signal Transduction	1	3.4×	0.267	MYO19

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
GPI anchor biosynthetic process	2	330.4×	1e-04	PIGM, PIGW
mitochondrion migration along actin filament	1	5617.3×	8e-04	MYO19
GPI anchor metabolic process	1	1872.4×	0.002	PIGW
mitocytosis	1	936.2×	0.002	MYO19
regulation of mitochondrial fission	1	702.2×	0.003	MYO19
regulation of cytokinesis	1	140.4×	0.011	MYO19
actin filament organization	1	39.6×	0.031	MYO19
protein localization to plasma membrane	1	36.2×	0.031	PIGW
endocytosis	1	31.7×	0.031	MYO19

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 3

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PIGM	0	0
PIGW	0	0
MYO19	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
PIGW	1	ADMET:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	PIGM, PIGW, MYO19

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
PIGM	0	—
PIGW	1	—
MYO19	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.