Action myoclonus-renal failure syndrome

Summary

Action myoclonus-renal failure syndrome (MONDO:0009699) is a disease caused by SCARB2 (GenCC Definitive), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SCARB2 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 126

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		38	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	action myoclonus-renal failure syndrome
Mondo ID	MONDO:0009699
OMIM	254900
Orphanet	163696
DOID	DOID:0111444
SNOMED CT	764453009
UMLS	C0751779
MedGen	155629
GARD	0017000
Is cancer (heuristic)	no

Also known as: action myoclonus-renal failure syndrome · AMRF · epilepsy, progressive myoclonic 4, with or without renal failure · epilepsy, progressive myoclonic, 4, with or without renal failure · EPM4 · myoclonus-nephropathy syndrome · progressive myoclonic epilepsy type 4

Data availability: 126 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary neurological disease › progressive myoclonus epilepsy › action myoclonus-renal failure syndrome

Related subtypes (14): Lafora disease, Unverricht-Lundborg syndrome, MERRF syndrome, familial encephalopathy with neuroserpin inclusion bodies, neuronal ceroid lipofuscinosis 8 northern epilepsy variant, progressive myoclonic epilepsy type 3, epilepsy, progressive myoclonic, 1B, progressive myoclonic epilepsy type 6, progressive myoclonic epilepsy type 7, progressive myoclonic epilepsy type 8, progressive myoclonic epilepsy type 9, early-onset Lafora body disease, epilepsy, progressive myoclonic, 11, epilepsy, progressive myoclonic, 12

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

126 retrieved; paginated sample, class counts are floors:

59 uncertain significance, 15 pathogenic, 14 conflicting classifications of pathogenicity, 9 likely pathogenic, 9 likely benign, 7 benign/likely benign, 7 not provided, 4 pathogenic/likely pathogenic, 2 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1323553	NM_005506.4(SCARB2):c.1240_1241delAG (p.Ser414fs)	SCARB2	Pathogenic	no assertion criteria provided
1451782	NM_005506.4(SCARB2):c.235del (p.Glu79fs)	SCARB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
206709	NM_005506.4(SCARB2):c.361C>T (p.Arg121Ter)	SCARB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2088984	NM_005506.4(SCARB2):c.88C>T (p.Gln30Ter)	SCARB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
268138	NM_005506.4(SCARB2):c.666_670del (p.Tyr222_Asn224delinsTer)	SCARB2	Pathogenic	criteria provided, single submitter
268139	NM_005506.4(SCARB2):c.704+1G>A	SCARB2	Pathogenic	criteria provided, multiple submitters, no conflicts
268142	NM_005506.4(SCARB2):c.1016dup (p.His341fs)	SCARB2	Pathogenic	criteria provided, single submitter
268146	NM_005506.4(SCARB2):c.1270C>T (p.Arg424Ter)	SCARB2	Pathogenic	criteria provided, multiple submitters, no conflicts
30257	NM_005506.4(SCARB2):c.1114-2A>C	SCARB2	Pathogenic	no assertion criteria provided
30258	NM_005506.4(SCARB2):c.1258del (p.Glu420fs)	SCARB2	Pathogenic	no assertion criteria provided
4292546	NM_005506.4(SCARB2):c.994+1G>T	SCARB2	Pathogenic	criteria provided, single submitter
453288	NM_005506.4(SCARB2):c.367dup (p.Gln123fs)	SCARB2	Pathogenic	no assertion criteria provided
7376	NM_005506.4(SCARB2):c.1239+1G>T	SCARB2	Pathogenic	no assertion criteria provided
7377	NM_005506.4(SCARB2):c.434_435dup (p.Trp146fs)	SCARB2	Pathogenic	criteria provided, multiple submitters, no conflicts
7378	NM_005506.4(SCARB2):c.862C>T (p.Gln288Ter)	SCARB2	Pathogenic	criteria provided, multiple submitters, no conflicts
7379	NM_005506.4(SCARB2):c.533G>A (p.Trp178Ter)	SCARB2	Pathogenic	no assertion criteria provided
807488	NM_005506.4(SCARB2):c.134del (p.Asn45fs)	SCARB2	Pathogenic	criteria provided, single submitter
938927	NM_005506.4(SCARB2):c.1002dup (p.Ile335fs)	SCARB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
971806	NM_005506.4(SCARB2):c.956del (p.Leu319fs)	SCARB2	Pathogenic	criteria provided, multiple submitters, no conflicts
1700685	NM_144633.3(KCNH8):c.298T>C (p.Tyr100His)	KCNH8	Likely pathogenic	criteria provided, single submitter
1700686	NM_001283009.2(RTEL1):c.691G>T (p.Asp231Tyr)	RTEL1	Likely pathogenic	criteria provided, single submitter
1179028	NM_005506.4(SCARB2):c.994+2T>C	SCARB2	Likely pathogenic	criteria provided, single submitter
2433153	NM_005506.4(SCARB2):c.1114-2A>G	SCARB2	Likely pathogenic	criteria provided, single submitter
3590843	NM_005506.4(SCARB2):c.1353_1357del (p.Leu451fs)	SCARB2	Likely pathogenic	criteria provided, single submitter
3590860	NM_005506.4(SCARB2):c.117+2T>C	SCARB2	Likely pathogenic	criteria provided, single submitter
4070520	NM_005506.4(SCARB2):c.1240-2A>C	SCARB2	Likely pathogenic	criteria provided, single submitter
4086193	NM_005506.4(SCARB2):c.1042_1043del (p.Arg348fs)	SCARB2	Likely pathogenic	criteria provided, single submitter
993025	NM_005506.4(SCARB2):c.108dup (p.Ile37fs)	SCARB2	Likely pathogenic	no assertion criteria provided
1062169	NM_005506.4(SCARB2):c.24G>A (p.Thr8=)	SCARB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1104226	NM_005506.4(SCARB2):c.504T>A (p.Phe168Leu)	SCARB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 6 · 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
SCARB2	Definitive	Autosomal recessive	action myoclonus-renal failure syndrome	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SCARB2	Orphanet:163696	Action myoclonus-renal failure syndrome
SCARB2	Orphanet:308	Progressive myoclonic epilepsy type 1
SCARB2	Orphanet:77259	Gaucher disease type 1
RTEL1	Orphanet:1775	Dyskeratosis congenita
RTEL1	Orphanet:2032	Idiopathic pulmonary fibrosis
RTEL1	Orphanet:3322	Hoyeraal-Hreidarsson syndrome

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
SCARB2	HGNC:1665	ENSG00000138760	Q14108	Lysosome membrane protein 2	gencc,clinvar
RTEL1	HGNC:15888	ENSG00000258366	Q9NZ71	Regulator of telomere elongation helicase 1	clinvar
KCNH8	HGNC:18864	ENSG00000183960	Q96L42	Voltage-gated delayed rectifier potassium channel KCNH8	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SCARB2	Lysosome membrane protein 2	Acts as a lysosomal receptor for glucosylceramidase (GBA1) targeting.
RTEL1	Regulator of telomere elongation helicase 1	A probable ATP-dependent DNA helicase implicated in telomere-length regulation, DNA repair and the maintenance of genomic stability.
KCNH8	Voltage-gated delayed rectifier potassium channel KCNH8	Pore-forming (alpha) subunit of a voltage-gated delayed rectifier potassium channel that mediates outward-rectifying potassium currents.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · 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
Ion channel	1	37.2×	0.053
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SCARB2	Other/Unknown	no		CD36_fam, LimpII
RTEL1	Other/Unknown	no		Helicase-like_DEXD_c2, ATP-dep_Helicase_C, RAD3-like_helicase_DEAD
KCNH8	Ion channel	yes		PAS, cNMP-bd_dom, PAS-assoc_C

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
germinal epithelium of ovary	1
inferior vagus X ganglion	1
subthalamic nucleus	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
sural nerve	1
C1 segment of cervical spinal cord	1
corpus callosum	1
endothelial cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SCARB2	298	ubiquitous	marker	inferior vagus X ganglion, subthalamic nucleus, germinal epithelium of ovary
RTEL1	134	ubiquitous	yes	sural nerve, right hemisphere of cerebellum, cerebellar hemisphere
KCNH8	168	broad	marker	corpus callosum, endothelial cell, C1 segment of cervical spinal cord

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SCARB2	5,405
RTEL1	2,324
KCNH8	1,116

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SCARB2	Q14108	10
RTEL1	Q9NZ71	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KCNH8	Q96L42	64.41

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 21. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Cytosolic iron-sulfur cluster assembly	1	253.8×	0.025	RTEL1
Resolution of D-Loop Structures	1	211.5×	0.025	RTEL1
Extension of Telomeres	1	200.3×	0.025	RTEL1
Telomere Extension By Telomerase	1	152.3×	0.025	RTEL1
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)	1	131.3×	0.025	RTEL1
Telomere Maintenance	1	122.8×	0.025	RTEL1
Homology Directed Repair	1	102.9×	0.025	RTEL1
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	1	102.9×	0.025	RTEL1
DNA Double-Strand Break Repair	1	82.8×	0.026	RTEL1
Voltage gated Potassium channels	1	81.0×	0.026	KCNH8
Chromosome Maintenance	1	70.5×	0.027	RTEL1
HDR through Homologous Recombination (HRR)	1	63.4×	0.027	RTEL1
Potassium Channels	1	44.8×	0.036	KCNH8
Cargo recognition for clathrin-mediated endocytosis	1	34.9×	0.042	SCARB2
DNA Repair	1	32.8×	0.042	RTEL1
Clathrin-mediated endocytosis	1	28.4×	0.046	SCARB2
Neuronal System	1	14.8×	0.082	KCNH8
Membrane Trafficking	1	12.4×	0.088	SCARB2
Cell Cycle	1	12.0×	0.088	RTEL1
Vesicle-mediated transport	1	11.6×	0.088	SCARB2
Metabolism	1	3.9×	0.237	RTEL1

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
DNA strand displacement	1	5617.3×	0.001	RTEL1
regulation of carbohydrate catabolic process	1	5617.3×	0.001	SCARB2
negative regulation of telomere maintenance in response to DNA damage	1	5617.3×	0.001	RTEL1
positive regulation of telomeric loop disassembly	1	5617.3×	0.001	RTEL1
regulation of glucosylceramide catabolic process	1	5617.3×	0.001	SCARB2
telomeric loop disassembly	1	2808.7×	0.001	RTEL1
regulation of endosome organization	1	2808.7×	0.001	SCARB2
mitotic telomere maintenance via semi-conservative replication	1	1872.4×	0.002	RTEL1
negative regulation of t-circle formation	1	1872.4×	0.002	RTEL1
aminophospholipid transport	1	1404.3×	0.002	SCARB2
endosome to plasma membrane protein transport	1	1123.5×	0.002	SCARB2
positive regulation of telomere capping	1	1123.5×	0.002	RTEL1
positive regulation of telomere maintenance via telomere lengthening	1	936.2×	0.002	RTEL1
regulation of lysosome organization	1	936.2×	0.002	SCARB2
telomere maintenance in response to DNA damage	1	624.1×	0.003	RTEL1
negative regulation of DNA recombination	1	374.5×	0.005	RTEL1
regulation of double-strand break repair via homologous recombination	1	330.4×	0.005	RTEL1
protein targeting to lysosome	1	208.1×	0.008	SCARB2
positive regulation of telomere maintenance	1	170.2×	0.009	RTEL1
replication fork processing	1	140.4×	0.010	RTEL1
telomere maintenance	1	89.2×	0.015	RTEL1
regulation of membrane potential	1	77.0×	0.017	KCNH8
receptor-mediated endocytosis	1	73.9×	0.017	SCARB2
potassium ion transport	1	63.8×	0.019	KCNH8
positive regulation of neuron projection development	1	45.7×	0.024	SCARB2
potassium ion transmembrane transport	1	45.3×	0.024	KCNH8
autophagy	1	36.7×	0.029	SCARB2
sensory perception of sound	1	33.6×	0.030	SCARB2
DNA repair	1	21.3×	0.046	RTEL1

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
SCARB2	0	0
RTEL1	0	0
KCNH8	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
KCNH8	21	Binding:20, Toxicity:1

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	0
D	Druggable family + AlphaFold only, no drug	1	KCNH8
E	Difficult family or no structure, no drug	2	SCARB2, RTEL1

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)
SCARB2	0	—
RTEL1	0	—
KCNH8	21	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.