Brody myopathy

Summary

Brody myopathy (MONDO:0010977) is a disease caused by ATP2A1 (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ATP2A1 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 812

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	Brody myopathy
Mondo ID	MONDO:0010977
MeSH	C536607
OMIM	601003
Orphanet	53347
DOID	DOID:0050692
SNOMED CT	703530005
UMLS	C1832918
MedGen	371441
GARD	0009158
Is cancer (heuristic)	no

Also known as: Brody disease · Brody myopathy · sarcoplasmic reticulum -Ca2+ATPase deficiency

Data availability: 812 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 › Brody myopathy

Related subtypes (31): polyglucosan body myopathy, muscular atrophy, myopathy of extraocular muscle, acute quadriplegic myopathy, myofascial pain syndrome, myopathy with abnormal lipid metabolism, proximal myopathy with focal depletion of mitochondria, rippling muscle disease, myopathy due to myoadenylate deaminase deficiency, proximal myopathy with extrapyramidal signs, intermediate nemaline myopathy, hereditary inclusion-body myopathy, hereditary continuous muscle fiber activity, congenital myopathy, muscular dystrophy, metabolic myopathy, myositis disease, collagen 6-related myopathy, myopathy caused by variation in CRPPA, drug-induced myopathy, myopathy caused by variation in FKRP, myopathy caused by variation in FKTN, myopathy caused by variation in POMGNT1, myopathy caused by variation in POMGNT2, myopathy caused by variation in POMT1, myopathy caused by variation in POMT2, myopathy caused by variation in GMPPB, FHL1-related myopathy, myopathy, sarcoplasmic body, myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis 2, myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis

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:

258 uncertain significance, 257 likely benign, 35 pathogenic, 19 conflicting classifications of pathogenicity, 11 likely pathogenic, 10 benign, 7 pathogenic/likely pathogenic, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1031711	NM_004320.6(ATP2A1):c.1672_1673dup (p.Leu559fs)	ATP2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1073847	NC_000016.9:g.(?28888809)(28916830_?)del	ATP2A1	Pathogenic	criteria provided, single submitter
1073848	NC_000016.9:g.(?28900098)(28900284_?)del	ATP2A1	Pathogenic	criteria provided, single submitter
1323768	NM_004320.6(ATP2A1):c.592del (p.Arg198fs)	ATP2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1323776	NM_004320.6(ATP2A1):c.706C>T (p.Arg236Ter)	ATP2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1323799	NM_004320.6(ATP2A1):c.2574C>G (p.Tyr858Ter)	ATP2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1323957	NM_004320.6(ATP2A1):c.2574C>A (p.Tyr858Ter)	ATP2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323958	NM_004320.6(ATP2A1):c.324+1G>A	ATP2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1335911	NM_004320.6(ATP2A1):c.178del (p.Leu60fs)	ATP2A1	Pathogenic	no assertion criteria provided
1335913	NM_004320.6(ATP2A1):c.704T>A (p.Ile235Asn)	ATP2A1	Pathogenic	no assertion criteria provided
1360311	NM_004320.6(ATP2A1):c.1966C>T (p.Arg656Ter)	ATP2A1	Pathogenic	criteria provided, single submitter
1412650	NM_004320.6(ATP2A1):c.2262C>G (p.Tyr754Ter)	ATP2A1	Pathogenic	criteria provided, single submitter
1414230	NM_004320.6(ATP2A1):c.2056_2057del (p.Lys686fs)	ATP2A1	Pathogenic	criteria provided, single submitter
1451853	NM_004320.6(ATP2A1):c.2615_2618del (p.His872fs)	ATP2A1	Pathogenic	criteria provided, single submitter
1451898	NM_004320.6(ATP2A1):c.888dup (p.Lys297Ter)	ATP2A1	Pathogenic	criteria provided, single submitter
17802	NM_004320.6(ATP2A1):c.592C>T (p.Arg198Ter)	ATP2A1	Pathogenic	criteria provided, single submitter
17803	NM_004320.6(ATP2A1):c.2025C>A (p.Cys675Ter)	ATP2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
17805	NM_004320.6(ATP2A1):c.440del (p.Pro147fs)	ATP2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1938875	NM_004320.6(ATP2A1):c.1912C>T (p.Arg638Ter)	ATP2A1	Pathogenic	criteria provided, single submitter
1977444	NM_004320.6(ATP2A1):c.610A>T (p.Lys204Ter)	ATP2A1	Pathogenic	criteria provided, single submitter
2128534	NM_004320.6(ATP2A1):c.1575dup (p.Asn526Ter)	ATP2A1	Pathogenic	criteria provided, single submitter
2748911	NM_004320.6(ATP2A1):c.1712dup (p.Lys572fs)	ATP2A1	Pathogenic	criteria provided, single submitter
3001177	NM_004320.6(ATP2A1):c.1465C>T (p.Arg489Ter)	ATP2A1	Pathogenic	criteria provided, single submitter
3009643	NM_004320.6(ATP2A1):c.1712del (p.Pro571fs)	ATP2A1	Pathogenic	criteria provided, single submitter
3016794	NM_004320.6(ATP2A1):c.2664_2665del (p.Cys888_Glu889delinsTer)	ATP2A1	Pathogenic	criteria provided, single submitter
3604261	NM_004320.6(ATP2A1):c.1553_1554del (p.Pro518fs)	ATP2A1	Pathogenic	criteria provided, single submitter
3656302	NM_004320.6(ATP2A1):c.787del (p.Val263fs)	ATP2A1	Pathogenic	criteria provided, single submitter
3706250	NM_004320.6(ATP2A1):c.1086dup (p.Val363fs)	ATP2A1	Pathogenic	criteria provided, single submitter
3896089	NM_004320.6(ATP2A1):c.1585C>T (p.Arg529Ter)	ATP2A1	Pathogenic	criteria provided, single submitter
392313	NM_004320.6(ATP2A1):c.1184+1G>A	ATP2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
ATP2A1	Strong	Autosomal recessive	Brody myopathy	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ATP2A1	Orphanet:53347	Brody myopathy
SH2B1	Orphanet:261197	Proximal 16p11.2 microdeletion syndrome
SH2B1	Orphanet:261222	Distal 16p11.2 microdeletion syndrome
SH2B1	Orphanet:329249	Severe early-onset obesity-insulin resistance syndrome due to SH2B1 deficiency

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
ATP2A1	HGNC:811	ENSG00000196296	O14983	Sarcoplasmic/endoplasmic reticulum calcium ATPase 1	gencc,clinvar
SH2B1	HGNC:30417	ENSG00000178188	Q9NRF2	SH2B adapter protein 1	clinvar
ATP2A1-AS1	HGNC:51370	ENSG00000260442		ATP2A1 antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ATP2A1	Sarcoplasmic/endoplasmic reticulum calcium ATPase 1	Key regulator of striated muscle performance by acting as the major Ca(2+) ATPase responsible for the reuptake of cytosolic Ca(2+) into the sarcoplasmic reticulum.
SH2B1	SH2B adapter protein 1	Adapter protein for several members of the tyrosine kinase receptor family.

Protein-family classification

Druggable: 0 · Difficult: 2 · 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
Scaffold/PPI	1	5.8×	0.482
Transcription factor	1	2.8×	0.482
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ATP2A1	Transcription factor	no		P_typ_ATPase, ATPase_P-typ_cation-transptr_N, P-type_ATPase_IIA
SH2B1	Scaffold/PPI	no		SH2, PH_domain, PH-like_dom_sf
ATP2A1-AS1	Other/Unknown	no

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	2
diaphragm	1
skeletal muscle tissue of rectus abdominis	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
muscle of leg	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ATP2A1	185	tissue_specific	marker	hindlimb stylopod muscle, skeletal muscle tissue of rectus abdominis, diaphragm
SH2B1	253	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
ATP2A1-AS1	166	ubiquitous	yes	hindlimb stylopod muscle, primordial germ cell in gonad, muscle of leg

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATP2A1	2,809
SH2B1	1,123
ATP2A1-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SH2B1	Q9NRF2	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ATP2A1	O14983	88.65

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 18. 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
Signaling by Leptin	1	519.1×	0.009	SH2B1
Reduction of cytosolic Ca++ levels	1	475.8×	0.009	ATP2A1
Prolactin receptor signaling	1	380.7×	0.009	SH2B1
Platelet calcium homeostasis	1	356.9×	0.009	ATP2A1
Pre-NOTCH Processing in Golgi	1	317.2×	0.009	ATP2A1
Hemostasis	2	36.0×	0.009	ATP2A1, SH2B1
Growth hormone receptor signaling	1	237.9×	0.011	SH2B1
Pre-NOTCH Expression and Processing	1	184.2×	0.012	ATP2A1
Platelet homeostasis	1	139.3×	0.014	ATP2A1
Ion transport by P-type ATPases	1	103.8×	0.016	ATP2A1
Ion homeostasis	1	102.0×	0.016	ATP2A1
Signaling by NOTCH	1	87.8×	0.017	ATP2A1
Cardiac conduction	1	54.4×	0.025	ATP2A1
Ion channel transport	1	48.0×	0.027	ATP2A1
Muscle contraction	1	38.6×	0.031	ATP2A1
Factors involved in megakaryocyte development and platelet production	1	33.2×	0.034	SH2B1
Transport of small molecules	1	12.6×	0.083	ATP2A1
Signal Transduction	1	5.1×	0.187	ATP2A1

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
maintenance of mitochondrion location	1	8426.0×	0.001	ATP2A1
positive regulation of fast-twitch skeletal muscle fiber contraction	1	4213.0×	0.001	ATP2A1
positive regulation of ATPase-coupled calcium transmembrane transporter activity	1	4213.0×	0.001	ATP2A1
positive regulation of calcium ion import into sarcoplasmic reticulum	1	4213.0×	0.001	ATP2A1
positive regulation of endoplasmic reticulum calcium ion concentration	1	2808.7×	0.001	ATP2A1
negative regulation of striated muscle contraction	1	2808.7×	0.001	ATP2A1
relaxation of skeletal muscle	1	2808.7×	0.001	ATP2A1
positive regulation of cardiac muscle cell contraction	1	2808.7×	0.001	ATP2A1
calcium ion import into sarcoplasmic reticulum	1	2808.7×	0.001	ATP2A1
negative regulation of endoplasmic reticulum calcium ion concentration	1	1404.3×	0.002	ATP2A1
regulation of striated muscle contraction	1	1053.2×	0.002	ATP2A1
regulation of DNA biosynthetic process	1	936.2×	0.002	SH2B1
positive regulation of mitochondrial calcium ion concentration	1	842.6×	0.002	ATP2A1
apoptotic mitochondrial changes	1	443.5×	0.004	ATP2A1
regulation of cardiac conduction	1	421.3×	0.004	ATP2A1
calcium ion import	1	401.2×	0.004	ATP2A1
positive regulation of mitotic nuclear division	1	271.8×	0.006	SH2B1
intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress	1	240.7×	0.006	ATP2A1
lamellipodium assembly	1	221.7×	0.006	SH2B1
cell motility	1	200.6×	0.007	SH2B1
positive regulation of SMAD protein signal transduction	1	191.5×	0.007	SH2B1
calcium ion transmembrane transport	1	105.3×	0.011	ATP2A1
monoatomic ion transmembrane transport	1	104.0×	0.011	ATP2A1
calcium ion transport	1	90.6×	0.012	ATP2A1
response to endoplasmic reticulum stress	1	83.4×	0.013	ATP2A1
intracellular calcium ion homeostasis	1	72.6×	0.014	ATP2A1
intracellular signal transduction	1	19.1×	0.052	SH2B1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ATP2A1	0	0
SH2B1	0	0
ATP2A1-AS1	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
ATP2A1	6	Binding:6

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	3	ATP2A1, SH2B1, ATP2A1-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)
ATP2A1	6	—
SH2B1	0	—
ATP2A1-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.