Leber congenital amaurosis 17

Summary

Leber congenital amaurosis 17 (MONDO:0014145) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 390

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Leber congenital amaurosis 17
Mondo ID	MONDO:0014145
OMIM	615360
DOID	DOID:0110217
UMLS	C3715164
MedGen	811616
GARD	0015950
Is cancer (heuristic)	no

Also known as: GDF6 Leber congenital amaurosis · LCA17 · Leber congenital amaurosis 17 · Leber congenital amaurosis caused by mutation in GDF6 · Leber congenital amaurosis type 17

Data availability: 390 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › Leber congenital amaurosis › Leber congenital amaurosis 17

Related subtypes (20): retinal aplasia, Leber congenital amaurosis 1, Leber congenital amaurosis 2, Leber congenital amaurosis 3, Leber congenital amaurosis 4, Leber congenital amaurosis 5, Leber congenital amaurosis 9, Leber congenital amaurosis 12, Leber congenital amaurosis 10, Leber congenital amaurosis 13, Leber congenital amaurosis 14, Leber congenital amaurosis 6, Leber congenital amaurosis 7, Leber congenital amaurosis 8, Leber congenital amaurosis 11, Leber congenital amaurosis 15, Leber congenital amaurosis 16, Leber congenital amaurosis 19, Leber congenital amaurosis with early-onset deafness, Leber congenital amaurosis 18

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

390 retrieved; paginated sample, class counts are floors:

197 uncertain significance, 148 likely benign, 22 conflicting classifications of pathogenicity, 15 benign, 7 benign/likely benign, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
60533	NM_001001557.4(GDF6):c.876G>Y (p.Glu292Asp)	GDF6	Pathogenic	no assertion criteria provided
1002016	NM_001001557.4(GDF6):c.536C>A (p.Pro179Gln)	GDF6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1023649	NM_001001557.4(GDF6):c.902A>G (p.Glu301Gly)	GDF6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1094356	NM_001001557.4(GDF6):c.407-3C>T	GDF6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1400072	NM_001001557.4(GDF6):c.923_928dup (p.306GA[3])	GDF6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1404300	NM_001001557.4(GDF6):c.959C>G (p.Pro320Arg)	GDF6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1938713	NM_001001557.4(GDF6):c.219C>A (p.Asp73Glu)	GDF6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1959955	NM_001001557.4(GDF6):c.454G>A (p.Val152Met)	GDF6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
286405	NM_001001557.4(GDF6):c.725C>G (p.Ala242Gly)	GDF6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2927707	NM_001001557.4(GDF6):c.625C>T (p.Pro209Ser)	GDF6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
364042	NM_001001557.4(GDF6):c.1304C>T (p.Ala435Val)	GDF6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
364044	NM_001001557.4(GDF6):c.957C>A (p.Ala319=)	GDF6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
364047	NM_001001557.4(GDF6):c.770C>T (p.Pro257Leu)	GDF6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
60534	NM_001001557.4(GDF6):c.169G>C (p.Asp57His)	GDF6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
707560	NM_001001557.4(GDF6):c.24C>G (p.Leu8=)	GDF6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
707574	NM_001001557.4(GDF6):c.112G>C (p.Gly38Arg)	GDF6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
836995	NM_001001557.4(GDF6):c.815C>T (p.Pro272Leu)	GDF6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
8371	NM_001001557.4(GDF6):c.746C>A (p.Ala249Glu)	GDF6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
8372	NM_001001557.4(GDF6):c.866T>C (p.Leu289Pro)	GDF6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
8373	NM_001001557.4(GDF6):c.1271A>G (p.Lys424Arg)	GDF6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
863448	NM_001001557.4(GDF6):c.322G>A (p.Ala108Thr)	GDF6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
914077	NM_001001557.4(GDF6):c.250G>A (p.Glu84Lys)	GDF6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
914078	NM_001001557.4(GDF6):c.18C>T (p.Val6=)	GDF6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1001816	NM_001001557.4(GDF6):c.1310A>G (p.Asn437Ser)	GDF6	Uncertain significance	criteria provided, single submitter
1002101	NM_001001557.4(GDF6):c.896C>T (p.Ser299Leu)	GDF6	Uncertain significance	criteria provided, single submitter
1007576	NM_001001557.4(GDF6):c.611C>T (p.Pro204Leu)	GDF6	Uncertain significance	criteria provided, single submitter
1008100	NM_001001557.4(GDF6):c.377C>T (p.Thr126Met)	GDF6	Uncertain significance	criteria provided, multiple submitters, no conflicts
1008463	NM_001001557.4(GDF6):c.272G>C (p.Arg91Pro)	GDF6	Uncertain significance	criteria provided, multiple submitters, no conflicts
1015372	NM_001001557.4(GDF6):c.323C>A (p.Ala108Asp)	GDF6	Uncertain significance	criteria provided, single submitter
1026389	NM_001001557.4(GDF6):c.1229T>G (p.Met410Arg)	GDF6	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · 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
GDF6	Supportive	Autosomal dominant	Leber congenital amaurosis	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GDF6	Orphanet:2345	Isolated Klippel-Feil syndrome
GDF6	Orphanet:3237	Multiple synostoses syndrome
GDF6	Orphanet:65	Leber congenital amaurosis
GDF6	Orphanet:98938	Colobomatous microphthalmia

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
GDF6	HGNC:4221	ENSG00000156466	Q6KF10	Growth/differentiation factor 6	gencc,clinvar
PLEKHF2	HGNC:20757	ENSG00000175895	Q9H8W4	Pleckstrin homology domain-containing family F member 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GDF6	Growth/differentiation factor 6	Growth factor that controls proliferation and cellular differentiation in the retina and bone formation.
PLEKHF2	Pleckstrin homology domain-containing family F member 2	May play a role in early endosome fusion upstream of RAB5, hence regulating receptor trafficking and fluid-phase transport.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GDF6	Other/Unknown	no		TGF-b_propeptide, TGF-b_C, TGF-beta-like
PLEKHF2	Transcription factor	no		Znf_FYVE, PH_domain, Znf_FYVE_PHD

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
placenta	1
primordial germ cell in gonad	1
ventricular zone	1
oocyte	1
secondary oocyte	1
upper leg skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GDF6	104	broad	marker	placenta, primordial germ cell in gonad, ventricular zone
PLEKHF2	268	ubiquitous	marker	secondary oocyte, oocyte, upper leg skin

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PLEKHF2	1,324
GDF6	1,127

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PLEKHF2	Q9H8W4	87.36
GDF6	Q6KF10	70.88

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cell migration involved in metanephros development	1	8426.0×	0.002	GDF6
retinal cell apoptotic process	1	4213.0×	0.002	GDF6
epithelial cell migration	1	468.1×	0.008	GDF6
activin receptor signaling pathway	1	443.5×	0.008	GDF6
positive regulation of chondrocyte differentiation	1	401.2×	0.008	GDF6
positive regulation of p38MAPK cascade	1	312.1×	0.009	GDF6
metanephros development	1	255.3×	0.009	GDF6
positive regulation of SMAD protein signal transduction	1	191.5×	0.009	GDF6
endosome organization	1	187.2×	0.009	PLEKHF2
endosome to lysosome transport	1	168.5×	0.009	PLEKHF2
BMP signaling pathway	1	100.3×	0.013	GDF6
positive regulation of neuron differentiation	1	99.1×	0.013	GDF6
fat cell differentiation	1	90.6×	0.014	GDF6
protein transport	1	21.9×	0.051	PLEKHF2
apoptotic process	1	14.3×	0.070	GDF6
positive regulation of DNA-templated transcription	1	14.0×	0.070	GDF6

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
GDF6	0	0
PLEKHF2	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	GDF6, PLEKHF2

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)
GDF6	0	—
PLEKHF2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.