Nemaline myopathy 8

Summary

Nemaline myopathy 8 (MONDO:0014138) is a disease caused by KLHL40 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: KLHL40 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 496

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	nemaline myopathy 8
Mondo ID	MONDO:0014138
OMIM	615348
DOID	DOID:0110930
NCIT	C129871
UMLS	C3809209
MedGen	815539
GARD	0015946
Is cancer (heuristic)	no

Also known as: KLHL40 nemaline myopathy · NEM8 · nemaline myopathy 8 · nemaline myopathy caused by mutation in KLHL40 · nemaline myopathy type 8

Data availability: 496 ClinVar variants · 5 GenCC gene-disease records · 2 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › severe congenital nemaline myopathy › nemaline myopathy 8

Related subtypes (4): congenital myopathy 2a, typical, autosomal dominant, nemaline myopathy 2, nemaline myopathy 9, nemaline myopathy 10

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

496 retrieved; paginated sample, class counts are floors:

242 uncertain significance, 178 likely benign, 27 pathogenic, 13 benign, 12 likely pathogenic, 12 conflicting classifications of pathogenicity, 8 benign/likely benign, 4 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1029196	NM_152393.4(KLHL40):c.1489C>T (p.Gln497Ter)	KLHL40	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1029197	NM_152393.4(KLHL40):c.703G>T (p.Glu235Ter)	KLHL40	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1172562	NM_152393.4(KLHL40):c.1608-1G>A	KLHL40	Pathogenic	criteria provided, multiple submitters, no conflicts
1320051	NM_152393.4(KLHL40):c.1281_1294del (p.Cys428fs)	KLHL40	Pathogenic	criteria provided, single submitter
1388572	NM_152393.4(KLHL40):c.58C>T (p.Gln20Ter)	KLHL40	Pathogenic	criteria provided, single submitter
1405293	NM_152393.4(KLHL40):c.223G>T (p.Glu75Ter)	KLHL40	Pathogenic	criteria provided, single submitter
1411479	NM_152393.4(KLHL40):c.928del (p.Leu310fs)	KLHL40	Pathogenic	criteria provided, single submitter
1454686	NM_152393.4(KLHL40):c.173del (p.Phe58fs)	KLHL40	Pathogenic	criteria provided, single submitter
1458028	NM_152393.4(KLHL40):c.205_214del (p.Ala69fs)	KLHL40	Pathogenic	criteria provided, single submitter
1971874	NM_152393.4(KLHL40):c.275C>G (p.Ser92Ter)	KLHL40	Pathogenic	criteria provided, single submitter
2176697	NM_152393.4(KLHL40):c.1292C>A (p.Ser431Ter)	KLHL40	Pathogenic	criteria provided, single submitter
2576958	NM_152393.4(KLHL40):c.270C>G (p.Tyr90Ter)	KLHL40	Pathogenic	no assertion criteria provided
2703307	NM_152393.4(KLHL40):c.1608-1G>C	KLHL40	Pathogenic	criteria provided, single submitter
2826151	NM_152393.4(KLHL40):c.1450dup (p.Asp484fs)	KLHL40	Pathogenic	criteria provided, single submitter
3652953	NM_152393.4(KLHL40):c.1302C>A (p.Cys434Ter)	KLHL40	Pathogenic	criteria provided, single submitter
3720495	NM_152393.4(KLHL40):c.134del (p.Pro45fs)	KLHL40	Pathogenic	criteria provided, single submitter
423767	NM_152393.4(KLHL40):c.1498C>T (p.Arg500Cys)	KLHL40	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4727795	NM_152393.4(KLHL40):c.301_304dup (p.Gln102fs)	KLHL40	Pathogenic	criteria provided, single submitter
4750508	NM_152393.4(KLHL40):c.586G>T (p.Glu196Ter)	KLHL40	Pathogenic	criteria provided, single submitter
4778318	NM_152393.4(KLHL40):c.815dup (p.Lys273fs)	KLHL40	Pathogenic	criteria provided, single submitter
541327	NM_152393.4(KLHL40):c.1395C>A (p.Tyr465Ter)	KLHL40	Pathogenic	criteria provided, single submitter
60512	NM_152393.4(KLHL40):c.1582G>A (p.Glu528Lys)	KLHL40	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
60513	NM_152393.4(KLHL40):c.1405G>T (p.Gly469Cys)	KLHL40	Pathogenic	criteria provided, single submitter
60514	NM_152393.4(KLHL40):c.602G>T (p.Trp201Leu)	KLHL40	Pathogenic	no assertion criteria provided
60515	NM_152393.4(KLHL40):c.1612G>C (p.Ala538Pro)	KLHL40	Pathogenic	no assertion criteria provided
60516	NM_152393.4(KLHL40):c.602G>A (p.Trp201Ter)	KLHL40	Pathogenic	criteria provided, multiple submitters, no conflicts
650910	NM_152393.4(KLHL40):c.818dup (p.Lys275fs)	KLHL40	Pathogenic	criteria provided, single submitter
658674	NM_152393.4(KLHL40):c.631del (p.Ala211fs)	KLHL40	Pathogenic	criteria provided, single submitter
846771	NM_152393.4(KLHL40):c.1516A>C (p.Thr506Pro)	KLHL40	Pathogenic	criteria provided, multiple submitters, no conflicts
952701	NM_152393.4(KLHL40):c.544_545del (p.Ser182fs)	KLHL40	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
KLHL40	Definitive	Autosomal recessive	nemaline myopathy 8	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KLHL40	Orphanet:171430	Severe congenital nemaline myopathy

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KLHL40	HGNC:30372	ENSG00000157119	Q2TBA0	Kelch-like protein 40	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KLHL40	Kelch-like protein 40	Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that acts as a key regulator of skeletal muscle development.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KLHL40	Other/Unknown	no		BTB/POZ_dom, Kelch_1, SKP1/BTB/POZ_sf

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gastrocnemius	1
hindlimb stylopod muscle	1
skeletal muscle tissue of rectus abdominis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KLHL40	114	tissue_specific	marker	gastrocnemius, skeletal muscle tissue of rectus abdominis, hindlimb stylopod muscle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KLHL40	1,156

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KLHL40	Q2TBA0	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

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
skeletal muscle fiber differentiation	1	1685.2×	0.004	KLHL40
skeletal muscle fiber development	1	543.6×	0.006	KLHL40
negative regulation of proteasomal ubiquitin-dependent protein catabolic process	1	401.2×	0.006	KLHL40
negative regulation of protein ubiquitination	1	285.6×	0.006	KLHL40
positive regulation of protein ubiquitination	1	213.3×	0.006	KLHL40
positive regulation of proteasomal ubiquitin-dependent protein catabolic process	1	210.7×	0.006	KLHL40
proteasome-mediated ubiquitin-dependent protein catabolic process	1	52.2×	0.019	KLHL40

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KLHL40	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
KLHL40	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	KLHL40

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)
KLHL40	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.