Congenital myasthenic syndrome 17

Summary

Congenital myasthenic syndrome 17 (MONDO:0014578) is a disease caused by LRP4 (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: LRP4 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 1,217

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital myasthenic syndrome 17
Mondo ID	MONDO:0014578
OMIM	616304
DOID	DOID:0110674
UMLS	C4225377
MedGen	895078
GARD	0016080
Is cancer (heuristic)	no

Also known as: CMS17 · congenital myasthenic syndrome caused by mutation in LRP4 · congenital myasthenic syndrome type 17 · LRP4 congenital myasthenic syndrome · myasthenic syndrome, congenital, 17 · myasthenic syndrome, congenital, type 17

Data availability: 1,217 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › postsynaptic congenital myasthenic syndrome › congenital myasthenic syndrome 17

Related subtypes (13): congenital myasthenic syndrome 10, congenital myasthenic syndrome 1A, congenital myasthenic syndrome 16, congenital myasthenic syndrome 8, congenital myasthenic syndrome 2A, congenital myasthenic syndrome 2C, congenital myasthenic syndrome 3A, congenital myasthenic syndrome 3B, congenital myasthenic syndrome 3C, congenital myasthenic syndrome 9, congenital myasthenic syndrome 11, congenital myasthenic syndrome 19, congenital myasthenic syndrome 4

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

600 retrieved; paginated sample, class counts are floors:

299 uncertain significance, 253 likely benign, 24 conflicting classifications of pathogenicity, 9 benign, 7 benign/likely benign, 4 pathogenic, 3 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1180722	NM_002334.4(LRP4):c.3698A>C (p.Glu1233Ala)	LRP4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323250	NM_002334.4(LRP4):c.2830C>T (p.Gln944Ter)	LRP4	Pathogenic	criteria provided, multiple submitters, no conflicts
1393202	NM_002334.4(LRP4):c.2260C>T (p.Arg754Ter)	LRP4	Pathogenic	criteria provided, single submitter
2112258	NM_002334.4(LRP4):c.2498del (p.Thr833fs)	LRP4	Pathogenic	criteria provided, single submitter
2921833	NM_002334.4(LRP4):c.1850del (p.Ala617fs)	LRP4	Pathogenic	criteria provided, single submitter
1179057	NM_002334.4(LRP4):c.1560G>A (p.Trp520Ter)	LRP4	Likely pathogenic	criteria provided, single submitter
1179202	NM_002334.4(LRP4):c.1184-1G>A	LRP4	Likely pathogenic	criteria provided, single submitter
2119457	NM_002334.4(LRP4):c.3699+1G>A	LRP4	Likely pathogenic	criteria provided, single submitter
1032815	NM_002334.4(LRP4):c.4245C>T (p.Asn1415=)	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1128252	NM_002334.4(LRP4):c.4404T>C (p.Asn1468=)	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1306610	NM_002334.4(LRP4):c.1654A>T (p.Asn552Tyr)	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1460952	NM_002334.4(LRP4):c.2010G>A (p.Thr670=)	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1500445	NM_002334.4(LRP4):c.1584C>A (p.Thr528=)	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1512123	NM_002334.4(LRP4):c.1342A>G (p.Ile448Val)	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1519697	NM_002334.4(LRP4):c.1633C>T (p.Arg545Trp)	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1567023	NM_002334.4(LRP4):c.132C>T (p.Cys44=)	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1567152	NM_002334.4(LRP4):c.1932C>T (p.Phe644=)	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1581161	NM_002334.4(LRP4):c.2216-13G>A	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1590124	NM_002334.4(LRP4):c.390T>C (p.Asp130=)	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
194206	NM_002334.4(LRP4):c.1551T>C (p.Ala517=)	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1946922	NM_002334.4(LRP4):c.2092+18G>A	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2048965	NM_002334.4(LRP4):c.3292T>A (p.Ser1098Thr)	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2062110	NM_002334.4(LRP4):c.5087+13A>G	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2079164	NM_002334.4(LRP4):c.3765A>G (p.Pro1255=)	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
211405	NM_002334.4(LRP4):c.3817C>A (p.Arg1273=)	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
281776	NM_002334.4(LRP4):c.639C>T (p.Asp213=)	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
282957	NM_002334.4(LRP4):c.5660C>G (p.Ser1887Cys)	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
284378	NM_002334.4(LRP4):c.4317C>T (p.Ala1439=)	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
285913	NM_002334.4(LRP4):c.2815-6T>G	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
286738	NM_002334.4(LRP4):c.3620A>G (p.Asn1207Ser)	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 27 · Orphanet: 4 · 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
CORIN	Strong	Autosomal recessive	congenital myasthenic syndrome 17	14
LRP4	Strong	Autosomal recessive	congenital myasthenic syndrome 17	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CORIN	Orphanet:275555	Preeclampsia
LRP4	Orphanet:3152	Sclerosteosis
LRP4	Orphanet:3258	Cenani-Lenz syndrome
LRP4	Orphanet:98913	Postsynaptic congenital myasthenic syndrome

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CORIN	HGNC:19012	ENSG00000145244	Q9Y5Q5	Atrial natriuretic peptide-converting enzyme	gencc,clinvar
LRP4	HGNC:6696	ENSG00000134569	O75096	Low-density lipoprotein receptor-related protein 4	gencc,clinvar
LRP4-AS1	HGNC:44128	ENSG00000247675		LRP4 antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CORIN	Atrial natriuretic peptide-converting enzyme	Serine-type endopeptidase involved in atrial natriuretic peptide (NPPA) and brain natriuretic peptide (NPPB) processing.
LRP4	Low-density lipoprotein receptor-related protein 4	Mediates SOST-dependent inhibition of bone formation.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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
Protease	1	12.2×	0.159
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CORIN	Protease	yes		SRCR, Trypsin_dom, LDrepeatLR_classA_rpt
LRP4	Other/Unknown	no		LDLR_classB_rpt, EGF, EGF-like_Ca-bd_dom
LRP4-AS1	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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cardiac muscle of right atrium	1
heart right ventricle	1
myocardium	1
dorsal motor nucleus of vagus nerve	1
medial globus pallidus	1
ventricular zone	1
colonic epithelium	1
male germ line stem cell (sensu Vertebrata) in testis	1
skin of leg	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CORIN	176	tissue_specific	marker	cardiac muscle of right atrium, heart right ventricle, myocardium
LRP4	242	ubiquitous	marker	ventricular zone, dorsal motor nucleus of vagus nerve, medial globus pallidus
LRP4-AS1	125	broad	marker	male germ line stem cell (sensu Vertebrata) in testis, colonic epithelium, skin of leg

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CORIN	1,291
LRP4	1,250
LRP4-AS1	0

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LRP4	O75096	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CORIN	Q9Y5Q5	70.20

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 3 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
Physiological factors	1	335.9×	0.009	CORIN
ECM proteoglycans	1	75.1×	0.020	LRP4
Extracellular matrix organization	1	31.6×	0.031	LRP4

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
positive regulation of presynaptic membrane organization	1	8426.0×	0.004	LRP4
regulation of systemic arterial blood pressure by atrial natriuretic peptide	1	2808.7×	0.004	CORIN
synaptic assembly at neuromuscular junction	1	2808.7×	0.004	LRP4
regulation of renal sodium excretion	1	2106.5×	0.004	CORIN
postsynaptic membrane assembly	1	1203.7×	0.004	LRP4
amyloid-beta clearance by cellular catabolic process	1	1053.2×	0.004	LRP4
skeletal muscle acetylcholine-gated channel clustering	1	936.2×	0.004	LRP4
positive regulation of skeletal muscle acetylcholine-gated channel clustering	1	936.2×	0.004	LRP4
presynaptic membrane assembly	1	842.6×	0.004	LRP4
generation of neurons	1	766.0×	0.004	LRP4
enzyme-linked receptor protein signaling pathway	1	648.1×	0.004	LRP4
negative regulation of axonogenesis	1	648.1×	0.004	LRP4
peptide hormone processing	1	468.1×	0.005	CORIN
regulation of cardiac conduction	1	421.3×	0.005	CORIN
proximal/distal pattern formation	1	324.1×	0.006	LRP4
positive regulation of Rac protein signal transduction	1	324.1×	0.006	LRP4
negative regulation of ossification	1	312.1×	0.006	LRP4
Rac protein signal transduction	1	280.9×	0.006	LRP4
dendrite morphogenesis	1	216.1×	0.007	LRP4
dorsal/ventral pattern formation	1	210.7×	0.007	LRP4
limb development	1	205.5×	0.007	LRP4
hair follicle development	1	191.5×	0.008	LRP4
regulation of postsynapse assembly	1	172.0×	0.008	LRP4
odontogenesis of dentin-containing tooth	1	150.5×	0.008	LRP4
embryonic digit morphogenesis	1	150.5×	0.008	LRP4
synapse organization	1	140.4×	0.009	LRP4
regulation of blood pressure	1	110.9×	0.011	CORIN
female pregnancy	1	105.3×	0.011	CORIN
kidney development	1	70.2×	0.016	LRP4
negative regulation of canonical Wnt signaling pathway	1	58.9×	0.018	LRP4

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 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
CORIN	0	0
LRP4	0	0
LRP4-AS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	0
D	Druggable family + AlphaFold only, no drug	1	CORIN
E	Difficult family or no structure, no drug	2	LRP4, LRP4-AS1

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)
CORIN	0	—
LRP4	0	—
LRP4-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.