Progressive myoclonic epilepsy type 6

Summary

Progressive myoclonic epilepsy type 6 (MONDO:0013526) is a disease caused by GOSR2 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: GOSR2 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 17

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		12	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	progressive myoclonic epilepsy type 6
Mondo ID	MONDO:0013526
OMIM	614018
Orphanet	280620
DOID	DOID:0111449
ICD-11	878291417
UMLS	C5190805
MedGen	1681379
GARD	0003872
Is cancer (heuristic)	no

Also known as: epilepsy, progressive myoclonic 6 · epilepsy, progressive myoclonic, 6 · epilepsy, progressive myoclonic, type 6 · EPM6 · GOSR2 progressive myoclonic epilepsy · GOSR2-related progressive myoclonus ataxia · North Sea progressive myoclonus epilepsy · PME type 6 · progressive myoclonic epilepsy caused by mutation in GOSR2 · progressive myoclonus epilepsy type 6

Data availability: 17 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 › progressive myoclonic epilepsy type 6

Related subtypes (14): Lafora disease, Unverricht-Lundborg syndrome, action myoclonus-renal failure 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 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

17 retrieved; paginated sample, class counts are floors:

6 conflicting classifications of pathogenicity, 3 benign, 3 pathogenic, 2 uncertain significance, 1 benign/likely benign, 1 pathogenic/likely pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
208982	NM_004287.5(GOSR2):c.485AGA[2] (p.Lys164del)	GOSR2	Pathogenic	no assertion criteria provided
211092	NM_004287.5(GOSR2):c.336+1G>A	GOSR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30406	NM_004287.5(GOSR2):c.430G>T (p.Gly144Trp)	GOSR2	Pathogenic	criteria provided, multiple submitters, no conflicts
997028	NM_004287.5(GOSR2):c.319C>T (p.Arg107Ter)	GOSR2	Pathogenic	no assertion criteria provided
424780	NM_004287.4(GOSR2):c.[336+1G>A];[430G>T]		Likely pathogenic	criteria provided, single submitter
137489	NM_004287.5(GOSR2):c.29+8C>T	GOSR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
323821	NM_004287.5(GOSR2):c.29+13C>T	GOSR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
323823	NM_004287.5(GOSR2):c.336+9G>A	GOSR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
695955	NM_004287.5(GOSR2):c.94+7A>C	GOSR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
997027	NM_004287.5(GOSR2):c.204-7A>G	LOC126862578	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
934652	NM_004287.5(GOSR2):c.336C>T (p.Asn112=)	LRRC37A2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
205631	NM_004287.5(GOSR2):c.509A>G (p.Asn170Ser)	GOSR2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3893144	NM_004287.5(GOSR2):c.3G>C (p.Met1Ile)	LRRC37A2	Uncertain significance	criteria provided, single submitter
137487	NM_004287.5(GOSR2):c.-30G>C	GOSR2	Benign	criteria provided, multiple submitters, no conflicts
205628	NM_004287.5(GOSR2):c.111C>T (p.Ile37=)	GOSR2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
129165	NM_004287.5(GOSR2):c.200G>A (p.Arg67Lys)	LRRC37A2	Benign	criteria provided, multiple submitters, no conflicts
193275	NM_004287.5(GOSR2):c.-12G>C	LRRC37A2	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
GOSR2	Strong	Autosomal recessive	progressive myoclonic epilepsy type 6	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GOSR2	Orphanet:280620	Progressive myoclonic epilepsy type 6

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GOSR2	HGNC:4431	ENSG00000108433	O14653	Golgi SNAP receptor complex member 2	gencc,clinvar
LRRC37A2	HGNC:32404	ENSG00000238083	A6NM11	Leucine-rich repeat-containing protein 37A2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GOSR2	Golgi SNAP receptor complex member 2	Involved in transport of proteins from the cis/medial-Golgi to the trans-Golgi network.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GOSR2	Other/Unknown	no		SNARE, GOSR2/Membrin/Bos1, v-SNARE_N_sf
LRRC37A2	Other/Unknown	no		Leu-rich_rpt, Leu-rich_rpt_typical-subtyp, LRRC37

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right testis	2
buccal mucosa cell	1
left testis	1
cerebellar hemisphere	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GOSR2	289	ubiquitous	marker	buccal mucosa cell, left testis, right testis
LRRC37A2	134		yes	right uterine tube, right testis, cerebellar hemisphere

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GOSR2	2,196
LRRC37A2	601

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GOSR2	O14653	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LRRC37A2	A6NM11	42.32

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 2 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Cargo concentration in the ER	1	335.9×	0.008	GOSR2
Intra-Golgi traffic	1	259.6×	0.008	GOSR2
XBP1(S) activates chaperone genes	1	215.5×	0.008	GOSR2
COPII-mediated vesicle transport	1	163.1×	0.008	GOSR2
COPI-mediated anterograde transport	1	109.8×	0.009	GOSR2

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
vesicle fusion	1	601.9×	0.003	GOSR2
intra-Golgi vesicle-mediated transport	1	526.6×	0.003	GOSR2
protein transport	1	43.9×	0.023	GOSR2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 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
GOSR2	0	0
LRRC37A2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	2	GOSR2, LRRC37A2

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
GOSR2	0	—
LRRC37A2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.