Nephrotic syndrome, type 3

Summary

Nephrotic syndrome, type 3 (MONDO:0012546) is a disease caused by PLCE1 (GenCC Definitive), with 4 cohort genes.

At a glance

• Causal gene: PLCE1 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 471

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	nephrotic syndrome, type 3
Mondo ID	MONDO:0012546
OMIM	610725
DOID	DOID:0080382
UMLS	C1853124
MedGen	377831
GARD	0015495
Is cancer (heuristic)	no

Also known as: nephrotic syndrome caused by mutation in PLCE1 · nephrotic syndrome, type 3 · NPHS3 · PLCE1 nephrotic syndrome

Data availability: 471 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › nephrotic syndrome › familial nephrotic syndrome › familial idiopathic steroid-resistant nephrotic syndrome › nephrotic syndrome, type 3

Related subtypes (13): nephrotic syndrome, type 2, focal segmental glomerulosclerosis 1, nephrotic syndrome, type 6, familial steroid-resistant nephrotic syndrome with sensorineural deafness, nephrotic syndrome, type 8, nephrotic syndrome, type 9, nephrotic syndrome, type 10, nephrotic syndrome, type 11, nephrotic syndrome, type 12, nephrotic syndrome, type 13, familial idiopathic steroid-resistant nephrotic syndrome with diffuse mesangial proliferation, familial idiopathic steroid-resistant nephrotic syndrome with minimal changes, familial idiopathic steroid-resistant nephrotic syndrome with diffuse mesangial sclerosis

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

471 retrieved; paginated sample, class counts are floors:

320 uncertain significance, 55 conflicting classifications of pathogenicity, 28 pathogenic, 23 benign, 17 likely benign, 13 likely pathogenic, 12 benign/likely benign, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
18422	NM_016341.4(PLCE1):c.6448C>T (p.Arg2150Ter)	NOC3L	Pathogenic	criteria provided, single submitter
1073097	NM_016341.4(PLCE1):c.4192dup (p.Leu1398fs)	PLCE1	Pathogenic	criteria provided, multiple submitters, no conflicts
1179035	NM_016341.4(PLCE1):c.4363dup (p.Thr1455fs)	PLCE1	Pathogenic	criteria provided, single submitter
1338991	NM_016341.4(PLCE1):c.4483C>T (p.Arg1495Ter)	PLCE1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1683684	NM_016341.4(PLCE1):c.3338_3339del (p.Lys1113fs)	PLCE1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1683685	NM_016341.4(PLCE1):c.4477C>T (p.Gln1493Ter)	PLCE1	Pathogenic	criteria provided, single submitter
1686081	NM_016341.4(PLCE1):c.1148C>A (p.Ser383Ter)	PLCE1	Pathogenic	criteria provided, single submitter
1686082	NM_016341.4(PLCE1):c.5168-1G>A	PLCE1	Pathogenic	criteria provided, single submitter
1687166	NM_016341.4(PLCE1):c.5363dup (p.Tyr1788Ter)	PLCE1	Pathogenic	criteria provided, single submitter
18423	NM_016341.4(PLCE1):c.961C>T (p.Arg321Ter)	PLCE1	Pathogenic	criteria provided, multiple submitters, no conflicts
18424	NM_016341.4(PLCE1):c.3736C>T (p.Arg1246Ter)	PLCE1	Pathogenic	criteria provided, multiple submitters, no conflicts
1929666	NM_016341.4(PLCE1):c.5979del (p.Gly1994fs)	PLCE1	Pathogenic	criteria provided, multiple submitters, no conflicts
2344	NM_016341.4(PLCE1):c.1146del (p.Ser383fs)	PLCE1	Pathogenic	no assertion criteria provided
2345	NM_016341.4(PLCE1):c.1477C>T (p.Arg493Ter)	PLCE1	Pathogenic	criteria provided, multiple submitters, no conflicts
2346	NM_016341.4(PLCE1):c.3346C>T (p.Arg1116Ter)	PLCE1	Pathogenic	no assertion criteria provided
2347	NM_016341.4(PLCE1):c.3846del (p.Leu1283fs)	PLCE1	Pathogenic	no assertion criteria provided
2348	NM_016341.4(PLCE1):c.4846C>T (p.Gln1616Ter)	PLCE1	Pathogenic	no assertion criteria provided
2349	NM_016341.4(PLCE1):c.5560C>T (p.Gln1854Ter)	PLCE1	Pathogenic	no assertion criteria provided
2350	NM_016341.4(PLCE1):c.4451C>T (p.Ser1484Leu)	PLCE1	Pathogenic	no assertion criteria provided
2577455	NM_016341.4(PLCE1):c.1350_1353del (p.Cys451fs)	PLCE1	Pathogenic	no assertion criteria provided
2579200	GRCh38/hg38 10q23.33(chr10:94131004-94133482)x0	PLCE1	Pathogenic	criteria provided, single submitter
2582223	NM_016341.4(PLCE1):c.3610C>T (p.Gln1204Ter)	PLCE1	Pathogenic	criteria provided, single submitter
2681758	NM_016341.4(PLCE1):c.5078_5079insGAGGAAAAGG (p.Ser1696fs)	PLCE1	Pathogenic	criteria provided, single submitter
3376124	NM_016341.4(PLCE1):c.3768del (p.Asn1257fs)	PLCE1	Pathogenic	criteria provided, single submitter
3764576	NM_016341.4(PLCE1):c.3982C>T (p.Gln1328Ter)	PLCE1	Pathogenic	criteria provided, single submitter
3775222	NM_016341.4(PLCE1):c.5407del (p.Met1803fs)	PLCE1	Pathogenic	criteria provided, single submitter
4277922	NM_016341.4(PLCE1):c.1115T>A (p.Leu372Ter)	PLCE1	Pathogenic	criteria provided, single submitter
4293375	NM_016341.4(PLCE1):c.789C>A (p.Tyr263Ter)	PLCE1	Pathogenic	criteria provided, single submitter
635315	NM_016341.4(PLCE1):c.3065G>A (p.Trp1022Ter)	PLCE1	Pathogenic	criteria provided, single submitter
800845	NM_016341.4(PLCE1):c.3058C>T (p.Gln1020Ter)	PLCE1	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
PLCE1	Definitive	Autosomal recessive	nephrotic syndrome, type 3	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PLCE1	Orphanet:656	Hereditary steroid-resistant nephrotic syndrome

Cohort genes → proteins

4 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PLCE1	HGNC:17175	ENSG00000138193	Q9P212	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase epsilon-1	gencc,clinvar
NOC3L	HGNC:24034	ENSG00000173145	Q8WTT2	Nucleolar complex protein 3 homolog	clinvar
PLCE1-AS1	HGNC:45193	ENSG00000268894		PLCE1 antisense RNA 1	clinvar
PLCE1-AS2	HGNC:51206	ENSG00000232913		PLCE1 antisense RNA 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PLCE1	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase epsilon-1	The production of the second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) is mediated by activated phosphatidylinositol-specific phospholipase C enzymes.
NOC3L	Nucleolar complex protein 3 homolog	May be required for adipogenesis.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.25

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
Enzyme (other)	1	3.0×	0.404
Other/Unknown	3	1.3×	0.404

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PLCE1	Enzyme (other)	yes	3.1.4.11	C2_dom, RA_dom, PLipase_C_PInositol-sp_X_dom
NOC3L	Other/Unknown	no		CCAAT-binding_factor, Noc3_N, ARM-type_fold
PLCE1-AS1	Other/Unknown	no
PLCE1-AS2	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

3 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	3
ventricular zone	2
metanephric glomerulus	1
renal glomerulus	1
calcaneal tendon	1
secondary oocyte	1
placenta	1
left testis	1
right testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PLCE1	271	broad	marker	renal glomerulus, metanephric glomerulus, ventricular zone
NOC3L	276	ubiquitous	marker	secondary oocyte, calcaneal tendon, male germ line stem cell (sensu Vertebrata) in testis
PLCE1-AS1	123	tissue_specific	yes	male germ line stem cell (sensu Vertebrata) in testis, placenta, ventricular zone
PLCE1-AS2	117	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, right testis, left testis

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NOC3L	3,036
PLCE1	1,560
PLCE1-AS1	0
PLCE1-AS2	0

Intra-cohort edges

A	B	Sources
NOC3L	PLCE1	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NOC3L	Q8WTT2	4
PLCE1	Q9P212	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 4 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Synthesis of IP3 and IP4 in the cytosol	1	423.0×	0.002	PLCE1

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
diacylglycerol biosynthetic process	1	936.2×	0.008	PLCE1
glomerulus development	1	648.1×	0.008	PLCE1
phosphatidylinositol metabolic process	1	443.5×	0.008	PLCE1
phosphatidylinositol-mediated signaling	1	351.1×	0.008	PLCE1
DNA replication initiation	1	312.1×	0.008	NOC3L
positive regulation of lamellipodium assembly	1	300.9×	0.008	PLCE1
release of sequestered calcium ion into cytosol	1	172.0×	0.012	PLCE1
epidermal growth factor receptor signaling pathway	1	123.9×	0.014	PLCE1
lipid catabolic process	1	122.1×	0.014	PLCE1
Ras protein signal transduction	1	102.8×	0.014	PLCE1
calcium-mediated signaling	1	91.6×	0.014	PLCE1
fat cell differentiation	1	90.6×	0.014	NOC3L
phospholipase C-activating G protein-coupled receptor signaling pathway	1	65.8×	0.017	PLCE1
intracellular signal transduction	1	19.1×	0.054	PLCE1
G protein-coupled receptor signaling pathway	1	18.1×	0.054	PLCE1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 4 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PLCE1	0	0
NOC3L	0	0
PLCE1-AS1	0	0
PLCE1-AS2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PLCE1	3.1.4.11	phosphoinositide phospholipase C

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

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	1	PLCE1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	NOC3L, PLCE1-AS1, PLCE1-AS2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PLCE1	0	—
NOC3L	0	—
PLCE1-AS1	0	—
PLCE1-AS2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.