LCA5

protein-coding

lebercilin LCA5

Gene summary

This gene encodes a protein that is thought to be involved in centrosomal or ciliary functions. Mutations in this gene cause Leber congenital amaurosis type V. Alternatively spliced transcript variants are described. [provided by RefSeq, Oct 2009]

Previous symbols:

C6orf152

MANE transcript

NM_001122769.3

Inheritance

AD, AR

ClinVar variants

P:180U:314B:307

Top phenotype

Leber congenital amaurosis 5

gnomAD constraint

pLI —, LoF o/e 0.41

Max pathogenic AF

—

Genomic locus

chr6:79,484,991-79,537,458

External References & Databases

Ensembl (ENSG00000135338)

Transcript & Mutation Effects

hg38 • Region Span ~52.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Leber congenital amaurosisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018998

Submitter: Orphanet

severe early-childhood-onset retinal dystrophySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009549

Submitter: Orphanet

Leber congenital amaurosis 5DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011473

Submitter: Ambry Genetics

Leber congenital amaurosis 5DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011473

Submitter: G2P

Leber congenital amaurosis 5STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011473

Submitter: Labcorp Genetics (formerly Invitae)

Leber congenital amaurosis 5STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011473

Submitter: PanelApp Australia

LCA5-related retinopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100445

Submitter: ClinGen

LCA5 was first reported in relation to autosomal recessive LCA5_related retinopathy in 2007, in a patient described as having Leber congenital amaurosis (LCA) (den Hollander et al., PMID: 17546029). LCA is a molecularly heterogeneous, early-onset, severe inherited retinal degeneration that typically presents within the first year of life with nystagmus and profound vision loss. Due to the heterogeneity of the phenotype and overla with other retinal conditions, such as retinitis pigmentosa, the disease entity curated is "LCA5-related retinopathy". Seven variants (nonsense, frameshift, and splicing) in six probands were curated. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. Majority of LCA-associated variants in the LCA5 gene are predicted loss-of-function variants (HGMD), however missense variants have also been reported to cause LCA (PMID: 24144451). Missense and splicing variants may also be associated with a later onset of retinal degeneration (PMID: 23946133). The mechanism of pathogenicity is known to be LOF. The LCA5 gene encodes lebercilin, a protein expressed in the connecting cilium of photoreceptors. Lebercilin interacts with other intraflagellar transport proteins required for the bidirectional movement of proteins and vesicles from the inner to outer segments of photoreceptors and is necessary for photoreceptor outer segment formation. This gene-disease association is also supported by protein expression in the retina, knockout animal models, and AAV-LCA5 rescue in the animal models (PMIDs: 21606596, 29673930, 32428231). In summary, LCA5 is definitively associated with autosomal recessive LCA5-related retinopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

Leber congenital amaurosis 5DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011473

Submitter: Natera

Clinical Genomic Database (CGD)

Leber congenital amaurosis 5AR

Manifestation: Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 10631161; 12642313; 17546029; 18334959; 20301475; 21850168

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to LCA5 variants in ClinVar

14 Conditions Cataloged

not providedTotal: 738

Leber congenital amaurosis 5Total: 234

Inborn genetic diseasesTotal: 93

not specifiedTotal: 76

LCA5-related disorderTotal: 73

Leber congenital amaurosisTotal: 50

Retinal dystrophyTotal: 11

Retinitis pigmentosaTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001122769.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			9 clinvar	288 clinvar		297
missense		8 clinvar	296 clinvar	17 clinvar	2 clinvar	323
nonsense	35 clinvar	25 clinvar	1 clinvar			61
start loss		4 clinvar				4
frameshift	48 clinvar	49 clinvar	5 clinvar			102
splice donor/acceptor (+/-2bp)	1 clinvar	10 clinvar	3 clinvar			14
Total	84	96	314	305	2	801

Highest pathogenic variant AF is 0.00005950772

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 15 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001122769.3	RefSeq	NP_001116241.1	7	MANE Select
ENST00000369846.9	Ensembl	ENSP00000358861.4	7	MANE Select
NM_181714.4	RefSeq	NP_859065.2	7	Standard
ENST00000392959.5	Ensembl	ENSP00000376686.1	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

intraciliary transport

Molecular Function

protein binding
protein-containing complex binding

Cellular Component

microtubule organizing center
cilium
axoneme

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000392959
Coding exons: 7
Length: 52468
Individuals with no LoFs: 125676
Homozygous LoFs: 1
Heterozygous LoFs: 59
Defined: 125736
p: 0.000239

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.621	370	338	1.10	0.0000175	4592
Missense (PolyPhen)		77	84.09	0.91569		1207
Synonymous	-1.14	143	127	1.13	0.00000656	1285
Loss of Function	3.09	13	31.8	0.408	0.00000198	406

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00015	0.00014	rare
Ashkenazi Jewish	0.0023	0.0022	notable
East Asian	0.00033	0.00033	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00015	0.00015	rare
South Asian	0.00017	0.00016	rare
Other	0.00065	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Might be involved in minus end-directed microtubule transport.;
Disease: DISEASE: Leber congenital amaurosis 5 (LCA5) [MIM:604537]: A severe dystrophy of the retina, typically becoming evident in the first years of life. Visual function is usually poor and often accompanied by nystagmus, sluggish or near-absent pupillary responses, photophobia, high hyperopia and keratoconus. {ECO:0000269|PubMed:17546029, ECO:0000269|PubMed:18000884, ECO:0000269|PubMed:18334959}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.111

Intolerance Scores

LoFtool: 0.730
RVIS EVS: -0.13
RVIS percentile EVS: 44.03

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.109

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	High
Cancer	Medium	Medium	Medium