Myotonia congenita, autosomal dominant

Summary

Myotonia congenita, autosomal dominant (MONDO:0008055) is a disease caused by CLCN1 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: CLCN1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 1,445

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	myotonia congenita, autosomal dominant
Mondo ID	MONDO:0008055
OMIM	160800
DOID	DOID:0081336
SNOMED CT	57938005, 8960007
UMLS	C2936781
MedGen	422446
GARD	0006176
Is cancer (heuristic)	no

Also known as: myotonia congenita, autosomal dominant · myotonia congenita, dominant · Thomsen and Becker disease · Thomsen disease

Data availability: 1,445 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › neuromuscular disease › muscular channelopathy › Thomsen and Becker disease › myotonia congenita, autosomal dominant

Related subtypes (1): myotonia congenita, autosomal recessive

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:

214 uncertain significance, 211 likely benign, 67 pathogenic, 38 conflicting classifications of pathogenicity, 32 likely pathogenic, 30 pathogenic/likely pathogenic, 8 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1000597	NM_000083.3(CLCN1):c.685G>A (p.Val229Met)	CLCN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1013567	NM_000083.3(CLCN1):c.1649C>G (p.Thr550Arg)	CLCN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069498	NM_000083.3(CLCN1):c.99C>A (p.Tyr33Ter)	CLCN1	Pathogenic	criteria provided, single submitter
1070234	NM_000083.3(CLCN1):c.360del (p.Leu121fs)	CLCN1	Pathogenic	criteria provided, single submitter
1070309	NM_000083.3(CLCN1):c.726T>A (p.Cys242Ter)	CLCN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070310	NM_000083.3(CLCN1):c.1235A>C (p.Gln412Pro)	CLCN1	Pathogenic	criteria provided, single submitter
1070311	NM_000083.3(CLCN1):c.1450T>C (p.Phe484Leu)	CLCN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072179	NM_000083.3(CLCN1):c.1472-2A>G	CLCN1	Pathogenic	criteria provided, single submitter
1073619	NM_000083.3(CLCN1):c.1909_1910del (p.Leu637fs)	CLCN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075850	NM_000083.3(CLCN1):c.200_215del (p.Glu67fs)	CLCN1	Pathogenic	criteria provided, single submitter
1175773	NM_000083.3(CLCN1):c.771T>A (p.Tyr257Ter)	CLCN1	Pathogenic	criteria provided, multiple submitters, no conflicts
1322089	NM_000083.3(CLCN1):c.697-1G>A	CLCN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1324083	NM_000083.3(CLCN1):c.47G>A (p.Trp16Ter)	CLCN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1324084	NM_000083.3(CLCN1):c.829T>C (p.Cys277Arg)	CLCN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1339487	NM_000083.3(CLCN1):c.1886T>C (p.Leu629Pro)	CLCN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1354004	NM_000083.3(CLCN1):c.2148dup (p.Glu717fs)	CLCN1	Pathogenic	criteria provided, multiple submitters, no conflicts
1363119	NM_000083.3(CLCN1):c.775C>T (p.Gln259Ter)	CLCN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1381093	NM_000083.3(CLCN1):c.443G>A (p.Trp148Ter)	CLCN1	Pathogenic	criteria provided, single submitter
1393878	NM_000083.3(CLCN1):c.1791_1792del (p.Gln597fs)	CLCN1	Pathogenic	criteria provided, single submitter
1402851	NM_000083.3(CLCN1):c.618C>A (p.Tyr206Ter)	CLCN1	Pathogenic	criteria provided, single submitter
1403542	NM_000083.3(CLCN1):c.989dup (p.Ala331fs)	CLCN1	Pathogenic	criteria provided, single submitter
1427478	NM_000083.3(CLCN1):c.2581del (p.Leu861fs)	CLCN1	Pathogenic	criteria provided, single submitter
1429319	NC_000007.13:g.(?143013209)(143049107_?)del	CLCN1	Pathogenic	criteria provided, single submitter
1432751	NM_000083.3(CLCN1):c.854-2A>G	CLCN1	Pathogenic	criteria provided, single submitter
1434202	NM_000083.3(CLCN1):c.1910T>A (p.Leu637Ter)	CLCN1	Pathogenic	criteria provided, single submitter
1449054	NM_000083.3(CLCN1):c.1281del (p.Leu427fs)	CLCN1	Pathogenic	criteria provided, single submitter
1452613	NM_000083.3(CLCN1):c.1401+1G>A	CLCN1	Pathogenic	criteria provided, single submitter
1453541	NM_000083.3(CLCN1):c.2045del (p.Ser682fs)	CLCN1	Pathogenic	criteria provided, single submitter
1454866	NM_000083.3(CLCN1):c.1269dup (p.Ile424fs)	CLCN1	Pathogenic	criteria provided, single submitter
1459630	NM_000083.3(CLCN1):c.2434C>T (p.Gln812Ter)	CLCN1	Pathogenic/Likely 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
CLCN1	Strong	Autosomal dominant	myotonia congenita, autosomal dominant	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CLCN1	Orphanet:614	Thomsen and Becker 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
CLCN1	HGNC:2019	ENSG00000188037	P35523	Chloride channel protein 1	gencc,clinvar
FAM131B	HGNC:22202	ENSG00000159784	Q86XD5	Protein FAM131B	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CLCN1	Chloride channel protein 1	Voltage-gated chloride channel involved in skeletal muscle excitability.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CLCN1	Other/Unknown	no		ClC, Cl_channel-1, Cl-channel_core
FAM131B	Other/Unknown	no		FAM131

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
hindlimb stylopod muscle	1
skeletal muscle tissue of rectus abdominis	1
triceps brachii	1
cerebellar hemisphere	1
cortical plate	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CLCN1	108	tissue_specific	marker	hindlimb stylopod muscle, triceps brachii, skeletal muscle tissue of rectus abdominis
FAM131B	193	broad	yes	cortical plate, right hemisphere of cerebellum, cerebellar hemisphere

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CLCN1	1,191
FAM131B	1,184

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CLCN1	P35523	9

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FAM131B	Q86XD5	55.50

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
Signaling by BRAF and RAF1 fusions	1	85.2×	0.015	FAM131B
Stimuli-sensing channels	1	68.0×	0.015	CLCN1

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
neuronal action potential propagation	1	1404.3×	0.003	CLCN1
chloride transport	1	455.5×	0.004	CLCN1
chloride transmembrane transport	1	237.3×	0.005	CLCN1
muscle contraction	1	208.1×	0.005	CLCN1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 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
CLCN1	0	0
FAM131B	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	0
E	Difficult family or no structure, no drug	2	CLCN1, FAM131B

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CLCN1	0	—
FAM131B	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.