Myofibrillar myopathy 8

Summary

Myofibrillar myopathy 8 (MONDO:0014993) is a disease caused by PYROXD1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: PYROXD1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 25

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	myofibrillar myopathy 8
Mondo ID	MONDO:0014993
OMIM	617258
DOID	DOID:0080308
UMLS	C4310645
MedGen	934612
GARD	0025045
Is cancer (heuristic)	no

Also known as: MFM8 · myofibrillar myopathy (disease) caused by mutation in PYROXD1 · myofibrillar myopathy 8 · myopathy, myofibrillar, 8 · myopathy, myofibrillar, type 8 · PYROXD1 myofibrillar myopathy (disease)

Data availability: 25 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › skeletal muscle disorder › myopathy › congenital myopathy › congenital structural myopathy › myofibrillar myopathy › myofibrillar myopathy 8

Related subtypes (12): central core myopathy, myofibrillar myopathy 1, myofibrillar myopathy 3, myofibrillar myopathy 4, myofibrillar myopathy 5, myofibrillar myopathy 6, fatal infantile hypertonic myofibrillar myopathy, myofibrillar myopathy 7, myofibrillar myopathy 11, myofibrillar myopathy 10, myopathy, myofibrillar, 12, infantile-onset, with cardiomyopathy, myopathy, myofibrillar, 13, with rimmed vacuoles

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

25 retrieved; paginated sample, class counts are floors:

9 benign, 7 pathogenic, 6 uncertain significance, 2 pathogenic/likely pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
3765540	NM_024854.5(PYROXD1):c.73del (p.Cys25fs)	LOC130007527	Pathogenic	criteria provided, single submitter
1452765	NM_024854.5(PYROXD1):c.892_895del (p.Val298fs)	PYROXD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2498274	NM_024854.5(PYROXD1):c.1061A>G (p.Tyr354Cys)	PYROXD1	Pathogenic	no assertion criteria provided
2498275	NM_024854.5(PYROXD1):c.334_337del (p.Leu112fs)	PYROXD1	Pathogenic	criteria provided, multiple submitters, no conflicts
372278	NM_024854.5(PYROXD1):c.285+1G>A	PYROXD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
372279	NM_024854.5(PYROXD1):c.1116G>C (p.Gln372His)	PYROXD1	Pathogenic	criteria provided, single submitter
372280	NM_024854.5(PYROXD1):c.464A>G (p.Asn155Ser)	PYROXD1	Pathogenic	criteria provided, multiple submitters, no conflicts
372281	NM_024854.5(PYROXD1):c.414+1G>A	PYROXD1	Pathogenic	no assertion criteria provided
372282	NM_024854.5(PYROXD1):c.1160_1163dup (p.Lys388fs)	PYROXD1	Pathogenic	no assertion criteria provided
1327287	NM_024854.5(PYROXD1):c.365G>A (p.Cys122Tyr)	PYROXD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1028346	NM_024854.5(PYROXD1):c.343G>A (p.Gly115Arg)	PYROXD1	Uncertain significance	criteria provided, single submitter
1031411	NM_024854.5(PYROXD1):c.617T>C (p.Ile206Thr)	PYROXD1	Uncertain significance	criteria provided, single submitter
1402733	NM_024854.5(PYROXD1):c.416A>C (p.Glu139Ala)	PYROXD1	Uncertain significance	criteria provided, single submitter
1934646	NM_024854.5(PYROXD1):c.394C>T (p.Arg132Cys)	PYROXD1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3062079	NM_024854.5(PYROXD1):c.750+5C>A	PYROXD1	Uncertain significance	criteria provided, single submitter
634627	NM_024854.5(PYROXD1):c.1004_1006del (p.Gly335del)	PYROXD1	Uncertain significance	criteria provided, single submitter
1277227	NM_024854.5(PYROXD1):c.-44T>C	LOC130007527	Benign	criteria provided, multiple submitters, no conflicts
1182978	NM_024854.5(PYROXD1):c.650-38T>C	PYROXD1	Benign	criteria provided, multiple submitters, no conflicts
1183477	NM_024854.5(PYROXD1):c.994-10T>C	PYROXD1	Benign	criteria provided, multiple submitters, no conflicts
1237631	NM_024854.5(PYROXD1):c.881-39A>G	PYROXD1	Benign	criteria provided, multiple submitters, no conflicts
1252658	NM_024854.5(PYROXD1):c.*49A>G	PYROXD1	Benign	criteria provided, multiple submitters, no conflicts
1253388	NM_024854.5(PYROXD1):c.84+40C>A	PYROXD1	Benign	criteria provided, multiple submitters, no conflicts
1260059	NM_024854.5(PYROXD1):c.751-36T>C	PYROXD1	Benign	criteria provided, multiple submitters, no conflicts
1262420	NM_024854.5(PYROXD1):c.165+22G>C	PYROXD1	Benign	criteria provided, multiple submitters, no conflicts
1278368	NM_024854.5(PYROXD1):c.489-23A>G	PYROXD1	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 0 · 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
PYROXD1	Definitive	Autosomal recessive	myofibrillar myopathy 8	5

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
PYROXD1	HGNC:26162	ENSG00000121350	Q8WU10	tRNA ligase complex-associated NAD(P)H dehydrogenase PYROXD1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PYROXD1	tRNA ligase complex-associated NAD(P)H dehydrogenase PYROXD1	Flavoprotein whose role is to protect RTCB, the catalytic subunit of the tRNA ligase complex (tRNA-LC) involved in tRNA splicing and unfolded protein response, from oxidative inactivation.

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)
PYROXD1	Other/Unknown	no		FAD/NAD-linked_Rdtase_dimer_sf, FAD/NAD-binding_dom, FAD/NAD-bd_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
buccal mucosa cell	1
colonic mucosa	1
mucosa of sigmoid colon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PYROXD1	295	ubiquitous	marker	buccal mucosa cell, mucosa of sigmoid colon, colonic mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PYROXD1	1,833

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PYROXD1	Q8WU10	2

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
tRNA exon ligation	1	5617.3×	4e-04	PYROXD1
cellular response to oxidative stress	1	154.6×	0.006	PYROXD1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
PYROXD1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	PYROXD1

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)
PYROXD1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.