Cardiac valvular defect, developmental

Summary

Cardiac valvular defect, developmental (MONDO:0008913) is a disease caused by PLD1 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: PLD1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 34

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cardiac valvular defect, developmental
Mondo ID	MONDO:0008913
MeSH	C565882
OMIM	212093
DOID	DOID:0080633
UMLS	C5774175
MedGen	1823949
Is cancer (heuristic)	no

Also known as: cardiac valvular defect, developmental · CVDD

Data availability: 34 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › disorder of development or morphogenesis › cardiac valvular defect, developmental

Related subtypes (189): precocious puberty, complex cortical dysplasia with other brain malformations, imperforate anus, microcephaly, demyelinating disease, hypospadias, bone development disease, primary basilar invagination, familial bicuspid aortic valve, camptodactyly of fingers, isolated congenital digital clubbing, aorta coarctation, gingival fibromatosis-progressive deafness syndrome, Eng-Strom syndrome, Morgagni-Stewart-Morel syndrome, familial partial lipodystrophy, Dunnigan type, megalodactyly, odontomatosis-aortae esophagus stenosis syndrome, otodental syndrome, oculodental syndrome, Rutherfurd type, spina bifida, steatocystoma multiplex-natal teeth syndrome, distal symphalangism, thumb deformity-alopecia-pigmentation anomaly syndrome, double uterus-hemivagina-renal agenesis syndrome, amelogenesis imperfecta type 1G, Bloom syndrome, isolated cerebellar hypoplasia/agenesis, cleft palate-stapes fixation-oligodontia syndrome, Jalili syndrome, craniodiaphyseal dysplasia, craniofacial dyssynostosis, deafness-oligodontia syndrome, duodenal atresia, Fowler syndrome, multiple intestinal atresia, natal teeth-intestinal pseudoobstruction-patent ductus syndrome, atresia of small intestine, mulibrey nanism, oculocerebral hypopigmentation syndrome, Cross type, familial osteodysplasia, Anderson type, pancreatic agenesis, postaxial polydactyly-dental and vertebral anomalies syndrome, familial primary pulmonary hypoplasia, renal tubular dysgenesis of genetic origin, Rothmund-Thomson syndrome, familial isolated congenital asplenia, subaortic stenosis, membranous, non-eruption of teeth-maxillary hypoplasia-genu valgum syndrome, corpus callosum agenesis-intellectual disability-coloboma-micrognathia syndrome, CK syndrome, Ogden syndrome, Nance-Horan syndrome, colonic atresia, Aicardi syndrome, torticollis-keloids-cryptorchidism-renal dysplasia syndrome, 46,XY complete gonadal dysgenesis, loose anagen syndrome, lung agenesis-heart defect-thumb anomalies syndrome, Chudley-McCullough syndrome, macrocephaly-autism syndrome, DNA ligase IV deficiency, horizontal gaze palsy with progressive scoliosis, cataract - congenital heart disease - neural tube defect syndrome, autosomal recessive frontotemporal pachygyria, craniofacial dysplasia - osteopenia syndrome, porencephaly-microcephaly-bilateral congenital cataract syndrome, congenital short bowel syndrome, familial median cleft of the upper and lower lips, progeroid features-hepatocellular carcinoma predisposition syndrome, progressive microcephaly-seizures-cortical blindness-developmental delay syndrome, aneurysm of sinus of Valsalva, blepharoptosis-cleft palate-ectrodactyly-dental anomalies syndrome, medullary sponge kidney, isolated congenital syngnathia, cleft lip and alveolus, diprosopus, T-B+ severe combined immunodeficiency due to IL-7Ralpha deficiency, high anorectal malformation, intermediate anorectal malformation, low anorectal malformation, microcephaly-polymicrogyria-corpus callosum agenesis syndrome, cordiform uterus, septate uterus, bicornuate uterus, uterine hypoplasia, agenesis and aplasia of uterine body, uterine cervical aplasia and agenesis, longitudinal vaginal septum, transverse vaginal septum, axial mesodermal dysplasia spectrum, multicystic dysplastic kidney, diabetic embryopathy, congenital microgastria, isolated cleft lip, cleft lip/palate, hereditary gingival fibromatosis, congenital bronchobiliary fistula, congenital hydrocephalus, maternal hyperthermia induced birth defects, diphallia, epibulbar lipodermoid-preauricular appendage-polythelia syndrome, bronchogenic cyst, duplication of urethra, hypohidrotic ectodermal dysplasia, Lowe-Kohn-Cohen syndrome, biliary atresia with splenic malformation syndrome, congenital pulmonary airway malformation, familial intestinal malrotation-facial anomalies syndrome, megalencephaly, cephalocele, cerebral cortical dysplasia, L1 syndrome, familial omphalocele syndrome with facial dysmorphism, penoscrotal transposition, pericardial and diaphragmatic defect, hypogonadotropic hypogonadism-severe microcephaly-sensorineural hearing loss-dysmorphism syndrome, congenital deformities of limbs, familial isolated clinodactyly of fingers, congenital shoulder dislocation, congenital elbow dislocation, congenital knee dislocation, congenital patella dislocation, macrodactyly of fingers, macrodactyly of toes, upper limb hypertrophy, lower limb hypertrophy, duplication of the pituitary gland, diencephalic-mesencephalic junction dysplasia, steroid dehydrogenase deficiency-dental anomalies syndrome, congenital achiasma, tracheal agenesis, renal agenesis, hypomyelination-cerebellar atrophy-hypoplasia of the corpus callosum syndrome, isolated splenogonadal fusion, Joubert syndrome, congenital generalized hypercontractile muscle stiffness syndrome, congenital bilateral absence of vas deferens, congenital portosystemic shunt, lissencephaly spectrum disorders, Berardinelli-Seip congenital lipodystrophy, congenital primary megaureter, craniorachischisis, vaginal atresia, bronchopulmonary dysplasia, dentinogenesis imperfecta-short stature-hearing loss-intellectual disability syndrome, aniridia, atypical Werner syndrome, X-linked intellectual disability-corpus callosum agenesis-spastic quadriparesis syndrome, anterior segment dysgenesis, congenital esophageal diverticulum, renal hypoplasia, renal dysplasia, overgrowth syndrome, developmental defect during embryogenesis, acalvaria, congenital aortic valve insufficiency, congenital anomaly of superior vena cava, congenital anomaly of hepatic vein, posterior hypospadias, isolated micropenis, isolated partial vaginal agenesis, anorectal malformation, pulmonary agenesis, congenital tricuspid malformation, Noonan syndrome and Noonan-related syndrome, coronary sinus stenosis, coronary sinus atresia, cartilage development disorder, syndactyly, polydactyly, brachydactyly, neurocristopathy, congenital absence of septum pellucidum, branchial arch disease, congenital anomaly of cardiovascular system, atelencephaly, aprosencephaly, aortic valve stenosis, hereditary lethal multiple congenital anomalies/dysmorphic syndrome, congenital agenesis of the scrotum, keratinization disease, lactation disease, COACH syndrome, constitutional delay of growth and puberty, isolated congenital femoral bifurcation, congenital peritoneal encapsulation, isolated short stature, congenital high airway obstruction syndrome

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

34 retrieved; paginated sample, class counts are floors:

13 uncertain significance, 8 likely pathogenic, 6 conflicting classifications of pathogenicity, 4 pathogenic, 2 benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3251798	NM_002662.5(PLD1):c.2034del (p.Trp678fs)	PLD1	Pathogenic	criteria provided, multiple submitters, no conflicts
4056489	NM_002662.5(PLD1):c.892C>T (p.Arg298Ter)	PLD1	Pathogenic	criteria provided, single submitter
426089	NM_002662.5(PLD1):c.1325A>C (p.His442Pro)	PLD1	Pathogenic	no assertion criteria provided
426091	NM_002662.5(PLD1):c.2882+2T>C	PLD1	Pathogenic	no assertion criteria provided
992233	NM_002662.5(PLD1):c.1219C>T (p.Arg407Ter)	PLD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1696830	NM_002662.5(PLD1):c.2023C>T (p.Arg675Trp)	PLD1	Likely pathogenic	criteria provided, single submitter
2441876	NM_002662.5(PLD1):c.2602C>T (p.Gln868Ter)	PLD1	Likely pathogenic	criteria provided, single submitter
2445423	NM_002662.5(PLD1):c.1062-2A>T	PLD1	Likely pathogenic	criteria provided, single submitter
2582520	NM_002662.5(PLD1):c.1403T>A (p.Val468Asp)	PLD1	Likely pathogenic	criteria provided, single submitter
3780441	NM_002662.5(PLD1):c.1061+1G>A	PLD1	Likely pathogenic	criteria provided, single submitter
3780442	NM_002662.5(PLD1):c.1708del (p.His570fs)	PLD1	Likely pathogenic	criteria provided, single submitter
426090	NM_002662.5(PLD1):c.1484_1485del (p.Thr495fs)	PLD1	Likely pathogenic	criteria provided, single submitter
992976	NM_002662.5(PLD1):c.498del (p.Ser167fs)	PLD1	Likely pathogenic	no assertion criteria provided
1033939	NM_002662.5(PLD1):c.2543+1G>T	PLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1033940	NM_002662.5(PLD1):c.2569A>G (p.Ile857Val)	PLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2582575	NM_002662.5(PLD1):c.3094C>T (p.Arg1032Ter)	PLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2722110	NM_002662.5(PLD1):c.2768G>A (p.Arg923His)	PLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3235803	NM_002662.5(PLD1):c.2593+1G>A	PLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
753438	NM_002662.5(PLD1):c.2852T>A (p.Phe951Tyr)	PLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1029620	NM_002662.5(PLD1):c.91C>T (p.Arg31Trp)	PLD1	Uncertain significance	criteria provided, single submitter
1030180	NM_002662.5(PLD1):c.1319G>A (p.Arg440His)	PLD1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1033938	NM_002662.5(PLD1):c.1543G>A (p.Ala515Thr)	PLD1	Uncertain significance	criteria provided, single submitter
1033941	NM_002662.5(PLD1):c.893G>A (p.Arg298Gln)	PLD1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1309145	NM_002662.5(PLD1):c.1982A>T (p.Asp661Val)	PLD1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1704369	NM_002662.5(PLD1):c.2500G>A (p.Gly834Ser)	PLD1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2434924	NM_002662.5(PLD1):c.2284A>G (p.Ile762Val)	PLD1	Uncertain significance	criteria provided, single submitter
2434925	NM_002662.5(PLD1):c.2134C>T (p.Arg712Trp)	PLD1	Uncertain significance	criteria provided, single submitter
2434926	NM_002662.5(PLD1):c.280A>G (p.Thr94Ala)	PLD1	Uncertain significance	criteria provided, single submitter
2671754	NM_002662.5(PLD1):c.3000+2T>A	PLD1	Uncertain significance	criteria provided, single submitter
3068185	NM_002662.5(PLD1):c.1042G>T (p.Glu348Ter)	PLD1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 15 · Orphanet: 1 · 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
PLD1	Definitive	Autosomal recessive	cardiac valvular defect, developmental	5
PRKCSH	Definitive	Autosomal recessive	cardiac valvular defect, developmental	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PRKCSH	Orphanet:2924	Isolated polycystic liver disease

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PLD1	HGNC:9067	ENSG00000075651	Q13393	Phospholipase D1	gencc,clinvar
PRKCSH	HGNC:9411	ENSG00000130175	P14314	Glucosidase 2 subunit beta	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PLD1	Phospholipase D1	Function as phospholipase selective for phosphatidylcholine.
PRKCSH	Glucosidase 2 subunit beta	Regulatory subunit of glucosidase II that cleaves sequentially the 2 innermost alpha-1,3-linked glucose residues from the Glc(2)Man(9)GlcNAc(2) oligosaccharide precursor of immature glycoproteins.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.5

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
Scaffold/PPI	1	8.6×	0.160
Enzyme (other)	1	6.0×	0.160

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PLD1	Scaffold/PPI	no	3.1.4.4	PX_dom, PLipase_D/transphosphatidylase, PH_domain
PRKCSH	Enzyme (other)	yes	3.2.1.207	EF_hand_dom, Man6P_isomerase_rcpt-bd_dom_sf, EF-hand-dom_pair

Expression context

Cohort genes with no expression data: 0.

2 cohort genes 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adrenal tissue	1
gall bladder	1
right adrenal gland cortex	1
olfactory bulb	1
stromal cell of endometrium	1
type B pancreatic cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PLD1	260	broad	marker	gall bladder, adrenal tissue, right adrenal gland cortex
PRKCSH	288	ubiquitous	marker	stromal cell of endometrium, type B pancreatic cell, olfactory bulb

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PLD1	2,282
PRKCSH	1,922

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PLD1	Q13393	2
PRKCSH	P14314	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Maturation of spike protein	1	951.7×	0.011	PRKCSH
Synthesis of PG	1	634.4×	0.011	PLD1
Advanced glycosylation endproduct receptor signaling	1	356.9×	0.011	PRKCSH
Calnexin/calreticulin cycle	1	356.9×	0.011	PRKCSH
Role of phospholipids in phagocytosis	1	228.4×	0.013	PLD1
N-glycan trimming in the ER and Calnexin/Calreticulin cycle	1	211.5×	0.013	PRKCSH
Regulation of CDH1 posttranslational processing and trafficking to plasma membrane	1	167.9×	0.013	PRKCSH
Synthesis of PA	1	146.4×	0.013	PLD1
Maturation of spike protein	1	132.8×	0.013	PRKCSH
RHOG GTPase cycle	1	74.2×	0.022	PLD1
Post-translational protein phosphorylation	1	50.1×	0.029	PRKCSH
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	43.3×	0.031	PRKCSH
RHOA GTPase cycle	1	37.3×	0.031	PLD1
CDC42 GTPase cycle	1	36.1×	0.031	PLD1
RAC1 GTPase cycle	1	30.5×	0.035	PLD1
Neutrophil degranulation	1	11.5×	0.085	PLD1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of microvillus assembly	1	1203.7×	0.005	PLD1
cellular response to nutrient	1	1053.2×	0.005	PLD1
phospholipid catabolic process	1	601.9×	0.005	PLD1
regulation of vesicle-mediated transport	1	561.7×	0.005	PLD1
regulation of synaptic vesicle cycle	1	561.7×	0.005	PLD1
N-glycan processing	1	366.4×	0.006	PRKCSH
phosphatidic acid biosynthetic process	1	255.3×	0.007	PLD1
positive regulation of translation	1	113.9×	0.013	PLD1
liver development	1	110.9×	0.013	PRKCSH
Ras protein signal transduction	1	102.8×	0.013	PLD1
small GTPase-mediated signal transduction	1	91.6×	0.013	PLD1
chemotaxis	1	68.0×	0.016	PLD1
intracellular signal transduction	1	19.1×	0.052	PRKCSH

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
PLD1	RALOXIFENE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PLD1	2	4
PRKCSH	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
RALOXIFENE	4	PLD1
HALOPEMIDE	2	PLD1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
PLD1	33	Binding:29, Functional:4
PRKCSH	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PLD1	3.1.4.4	phospholipase D
PRKCSH	3.2.1.207	mannosyl-oligosaccharide alpha-1,3-glucosidase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

2 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.

Compound	Max phase	Cohort target (bioactivity)
RALOXIFENE	4	PLD1
HALOPEMIDE	2	PLD1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PLD1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	PRKCSH
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PRKCSH	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.