Nemaline myopathy 6

Summary

Nemaline myopathy 6 (MONDO:0012237) is a disease caused by KBTBD13 (GenCC Definitive), with 3 cohort genes and 1 clinical trial.

At a glance

• Causal gene: KBTBD13 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 675
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	nemaline myopathy 6
Mondo ID	MONDO:0012237
MeSH	C538398
OMIM	609273
DOID	DOID:0110935
UMLS	C1836472
MedGen	373095
GARD	0015452
Is cancer (heuristic)	no

Also known as: KBTBD13 nemaline myopathy · NEM6 · nemaline myopathy 6 · nemaline myopathy caused by mutation in KBTBD13 · nemaline myopathy type 6

Data availability: 675 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › childhood-onset nemaline myopathy › nemaline myopathy 6

Related subtypes (5): congenital myopathy 2a, typical, autosomal dominant, nemaline myopathy 2, congenital myopathy 4B, autosomal recessive, congenital myopathy 23, nemaline myopathy 9

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:

376 uncertain significance, 126 likely benign, 39 conflicting classifications of pathogenicity, 34 benign, 21 benign/likely benign, 3 likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
31062	NM_001101362.3(KBTBD13):c.1222C>T (p.Arg408Cys)	KBTBD13	Pathogenic	criteria provided, single submitter
560063	Single allele	ANKDD1A	Likely pathogenic	criteria provided, single submitter
1709118	NM_001101362.3(KBTBD13):c.1170G>T (p.Lys390Asn)	KBTBD13	Likely pathogenic	criteria provided, multiple submitters, no conflicts
31061	NM_001101362.3(KBTBD13):c.1170G>C (p.Lys390Asn)	KBTBD13	Likely pathogenic	criteria provided, single submitter
1008965	NM_001101362.3(KBTBD13):c.1214C>T (p.Thr405Met)	KBTBD13	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1041732	NM_001101362.3(KBTBD13):c.499C>G (p.Pro167Ala)	KBTBD13	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1043553	NM_001101362.3(KBTBD13):c.403G>C (p.Glu135Gln)	KBTBD13	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1082246	NM_001101362.3(KBTBD13):c.830G>A (p.Arg277His)	KBTBD13	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1159843	NM_001101362.3(KBTBD13):c.1070G>T (p.Arg357Leu)	KBTBD13	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1335186	NM_001101362.3(KBTBD13):c.588G>A (p.Glu196=)	KBTBD13	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1432079	NM_001101362.3(KBTBD13):c.937C>T (p.Arg313Trp)	KBTBD13	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1472140	NM_001101362.3(KBTBD13):c.1126A>C (p.Thr376Pro)	KBTBD13	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1535156	NM_001101362.3(KBTBD13):c.451G>A (p.Ala151Thr)	KBTBD13	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1660364	NM_001101362.3(KBTBD13):c.1241A>G (p.Tyr414Cys)	KBTBD13	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1975519	NM_001101362.3(KBTBD13):c.458G>A (p.Arg153Gln)	KBTBD13	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2140881	NM_001101362.3(KBTBD13):c.23T>C (p.Leu8Pro)	KBTBD13	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2645454	NM_001101362.3(KBTBD13):c.27G>A (p.Val9=)	KBTBD13	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
316735	NM_001101362.3(KBTBD13):c.228C>G (p.Asp76Glu)	KBTBD13	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
316737	NM_001101362.3(KBTBD13):c.252C>T (p.Cys84=)	KBTBD13	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
316738	NM_001101362.3(KBTBD13):c.331G>A (p.Asp111Asn)	KBTBD13	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
316739	NM_001101362.3(KBTBD13):c.333C>G (p.Asp111Glu)	KBTBD13	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
316741	NM_001101362.3(KBTBD13):c.394G>A (p.Gly132Ser)	KBTBD13	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
316744	NM_001101362.3(KBTBD13):c.742C>T (p.Arg248Cys)	KBTBD13	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
316746	NM_001101362.3(KBTBD13):c.769G>C (p.Asp257His)	KBTBD13	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
316751	NM_001101362.3(KBTBD13):c.1101C>T (p.Cys367=)	KBTBD13	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
435545	NM_001101362.3(KBTBD13):c.244G>A (p.Val82Met)	KBTBD13	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
464351	NM_001101362.3(KBTBD13):c.251G>C (p.Cys84Ser)	KBTBD13	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
464353	NM_001101362.3(KBTBD13):c.2T>G (p.Met1Arg)	KBTBD13	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
464355	NM_001101362.3(KBTBD13):c.361G>C (p.Val121Leu)	KBTBD13	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
464357	NM_001101362.3(KBTBD13):c.393C>A (p.Asp131Glu)	KBTBD13	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 5 · 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
KBTBD13	Definitive	Autosomal dominant	nemaline myopathy 6	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KBTBD13	Orphanet:171439	Childhood-onset nemaline myopathy
MVK	Orphanet:29	Mevalonic aciduria
MVK	Orphanet:343	Hyperimmunoglobulinemia D with periodic fever
MVK	Orphanet:735	Porokeratosis of Mibelli
MVK	Orphanet:79152	Disseminated superficial actinic porokeratosis

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KBTBD13	HGNC:37227	ENSG00000234438	C9JR72	Kelch repeat and BTB domain-containing protein 13	gencc,clinvar
ANKDD1A	HGNC:28002	ENSG00000166839	Q495B1	Ankyrin repeat and death domain-containing protein 1A	clinvar
MVK	HGNC:7530	ENSG00000110921	Q03426	Mevalonate kinase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KBTBD13	Kelch repeat and BTB domain-containing protein 13	Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex.
MVK	Mevalonate kinase	Catalyzes the phosphorylation of mevalonate to mevalonate 5-phosphate, a key step in isoprenoid and cholesterol biosynthesis.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 1 · 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
Kinase	1	9.2×	0.246
Scaffold/PPI	1	5.8×	0.246
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KBTBD13	Other/Unknown	no		BTB/POZ_dom, Kelch_1, SKP1/BTB/POZ_sf
ANKDD1A	Scaffold/PPI	no		Death_dom, Ankyrin_rpt, DEATH-like_dom_sf
MVK	Kinase	yes	2.7.1.36	GHMP_knse_ATP-bd_CS, GHMP_kinase_N_dom, Mev_gal_kin

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
hindlimb stylopod muscle	1
primordial germ cell in gonad	1
skeletal muscle tissue	1
Brodmann (1909) area 23	1
left adrenal gland cortex	1
tendon of biceps brachii	1
lower esophagus mucosa	1
metanephros cortex	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KBTBD13	47	tissue_specific	yes	primordial germ cell in gonad, hindlimb stylopod muscle, skeletal muscle tissue
ANKDD1A	233	broad	marker	tendon of biceps brachii, Brodmann (1909) area 23, left adrenal gland cortex
MVK	271	ubiquitous	marker	lower esophagus mucosa, right lobe of liver, metanephros cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MVK	3,424
ANKDD1A	769
KBTBD13	606

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MVK	Q03426	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KBTBD13	C9JR72	90.56
ANKDD1A	Q495B1	89.79

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 14. 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
Cholesterol biosynthesis	1	571.0×	0.018	MVK
Lanosterol biosynthesis	1	380.7×	0.018	MVK
Regulation of cholesterol biosynthesis by SREBP (SREBF)	1	158.6×	0.027	MVK
Activation of gene expression by SREBF (SREBP)	1	129.8×	0.027	MVK
Metabolism of steroids	1	68.8×	0.041	MVK
Class I MHC mediated antigen processing & presentation	1	35.0×	0.066	KBTBD13
Neddylation	1	23.7×	0.084	KBTBD13
Antigen processing: Ubiquitination & Proteasome degradation	1	18.6×	0.092	KBTBD13
Metabolism of lipids	1	15.8×	0.092	MVK
Adaptive Immune System	1	14.9×	0.092	KBTBD13
Post-translational protein modification	1	9.6×	0.129	KBTBD13
Immune System	1	6.5×	0.165	KBTBD13
Metabolism of proteins	1	6.2×	0.165	KBTBD13
Metabolism	1	5.8×	0.165	MVK

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 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 the force of skeletal muscle contraction	1	1872.4×	0.002	KBTBD13
isopentenyl diphosphate biosynthetic process, mevalonate pathway	1	1872.4×	0.002	MVK
relaxation of skeletal muscle	1	1872.4×	0.002	KBTBD13
isoprenoid biosynthetic process	1	561.7×	0.004	MVK
cholesterol biosynthetic process	1	140.4×	0.013	MVK
negative regulation of inflammatory response	1	45.7×	0.032	MVK
actin filament organization	1	39.6×	0.032	KBTBD13
protein ubiquitination	1	13.8×	0.080	KBTBD13
signal transduction	1	5.3×	0.176	ANKDD1A

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
KBTBD13	0	0
ANKDD1A	0	0
MVK	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MVK	2.7.1.36	mevalonate kinase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	MVK
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	KBTBD13, ANKDD1A

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)
KBTBD13	0	—
ANKDD1A	0	—
MVK	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03211923	Not specified	UNKNOWN	Muscle Relaxation in Myopathies With Positive Muscle Phenomena