SPATA7

protein-coding

spermatogenesis associated 7

Gene summary

This gene, originally isolated from testis, is also expressed in retina. Mutations in this gene are associated with Leber congenital amaurosis and juvenile retinitis pigmentosa. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2010]

Previous symbols:

LCA3

MANE transcript

NM_018418.5

Inheritance

AR, AD

ClinVar variants

P:85U:264B:112

Top phenotype

Leber congenital amaurosis 3; Retitinitis pigmentosa, juvenile, SPATA7-related

gnomAD constraint

pLI —, LoF o/e 0.8

Max pathogenic AF

—

Genomic locus

chr14:88,384,924-88,470,350

External References & Databases

Ensembl (ENSG00000042317)

Transcript & Mutation Effects

hg38 • Region Span ~85.4 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Leber congenital amaurosis 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011415

Submitter: Labcorp Genetics (formerly Invitae)

inherited retinal dystrophyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019118

Submitter: ClinGen

*SPATA7* was first reported in relation to autosomal recessive retinal dystrophy in 2009 (Wang et al., PMID: 19268277). Affected individuals with *SPATA7*-related retinopathy show a wide range of age at onset, with a subset of cases presenting in infancy and others developing symptoms later in life. Common clinical features include nystagmus and severe visual loss, but significant inter- and inta-familial phenotypic variability has been described, including diagnoses of Leber congenital amaurosis and retinitis pigmentosa with variable age at onset. Per criteria outlined by the ClinGen Lumping & Splitting Working Group, the mode of inheritance (autosomal recessive) and molecular mechanism (biallelic *SPATA7* disruption) were found to be consistent among patients diagnosed with Leber congenital amaurosis 3 (MIM# 604232) or retinitis pigmentosa 94, variable age at onset, autosomal recessive (MIM# 604232). The phenotypic variability between cases appears to represent a spectrum of disease rather than separate disease entities. Therefore, cases caused by inherited biallelic *SPATA7* variants have been lumped into a single disease entity, referred to as SPATA7-related retinopathy. Nine variants (two nonsense, four frameshift, two missense and one in-frame indel) that have been reported in ten probands in six publications (PMIDs: 19268277, 22136677, 26854980, 29411205, 28481129, 21310915) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be biallelic loss-of-function. This gene-disease association is also supported by expression studies showing that *SPATA7* is expressed in multiple layers of the mouse retina (PMID: 19268277). More specifically, Eblimit et. al. show that *SPATA7* is localized to the connecting cilium of hTERT RPE-1 cells and mouse photoreceptors. This same group also provides evidence that *SPATA7* interacts with RPGRIP1, a protein that has previously been implicated in an X-linked form of retinal dystrophy. Finally, the relevant publication also discusses the findings in a *Spata7*-null mouse model. Mutant mice had severely reduced outer nuclear layer thickness, defective light response as measured by electroretinogram (ERG), as well as a reduction in expression and mislocalization of the RPGRIP1 and RHO proteins (PMID: 25398945). Another *Spata7* knockout mouse model supports these results (PMID: 35368022). In summary, *SPATA7* is definitively associated with autosomal recessive SPATA7-related retinopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time without the emergence of contradictory evidence. This classification was approved by the ClinGen Retina Gene Curation Expert Panel on August 1, 2024 (SOP Version 10).

Leber congenital amaurosis 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011415

Submitter: PanelApp Australia

severe early-childhood-onset retinal dystrophySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009549

Submitter: Orphanet

retinitis pigmentosaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019200

Submitter: Orphanet

Leber congenital amaurosisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018998

Submitter: Orphanet

Leber congenital amaurosis 3DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011415

Submitter: G2P

Leber congenital amaurosis 3DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011415

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Leber congenital amaurosis 3; Retitinitis pigmentosa, juvenile, SPATA7-relatedAR

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: 9799089; 18936139; 19268277; 21310915

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SPATA7 variants in ClinVar

15 Conditions Cataloged

Leber congenital amaurosis 3Total: 419

not providedTotal: 144

Inborn genetic diseasesTotal: 86

not specifiedTotal: 72

SPATA7-related disorderTotal: 65

Retinitis pigmentosaTotal: 44

Retinal dystrophyTotal: 40

Leber congenital amaurosisTotal: 14

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018418.5. 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			8 clinvar	90 clinvar	1 clinvar	99
missense	2 clinvar	4 clinvar	245 clinvar	20 clinvar	1 clinvar	272
nonsense	7 clinvar	10 clinvar				17
start loss		2 clinvar				2
frameshift	24 clinvar	19 clinvar	5 clinvar			48
splice donor/acceptor (+/-2bp)	5 clinvar	12 clinvar	6 clinvar			23
Total	38	47	264	110	2	461

Highest pathogenic variant AF is 0.000082157305

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 36 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_018418.5	RefSeq	NP_060888.2	12	MANE Select
ENST00000393545.9	Ensembl	ENSP00000377176.4	12	MANE Select
NM_001040428.4	RefSeq	NP_001035518.1	11	Standard
ENST00000045347.11	Ensembl	ENSP00000045347.7	13	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

visual perception
photoreceptor cell maintenance
response to stimulus
protein localization to photoreceptor outer segment
protein localization to photoreceptor connecting cilium

Molecular Function

protein binding

Cellular Component

nucleoplasm
mitochondrion
cytosol
axoneme
microtubule cytoskeleton

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000393545
Coding exons: 12
Length: 85427
Individuals with no LoFs: 125571
Homozygous LoFs: 1
Heterozygous LoFs: 176
Defined: 125748
p: 0.000704

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0409	311	313	0.993	0.0000160	3930
Missense (PolyPhen)		84	86.19	0.97459		1126
Synonymous	1.50	98	119	0.825	0.00000631	1101
Loss of Function	0.945	22	27.3	0.805	0.00000142	357

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00037	0.00037	rare
Latino/Admixed American	0.00035	0.00035	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.0066	0.0065	notable
Finnish	0.00019	0.00014	rare
European (Non-Finnish)	0.00026	0.00025	rare
South Asian	0.00016	0.00016	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in photoreceptor cells maintenance (By similarity). It is required for recruitment and proper localization of RPGRIP1 to the photoreceptor connecting cilium (CC), as well as protein trafficking across the CC to the outer segments (By similarity). {ECO:0000250|UniProtKB:Q80VP2}.;
Disease: DISEASE: Leber congenital amaurosis 3 (LCA3) [MIM:604232]: 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:19268277}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Retinitis pigmentosa autosomal recessive (ARRP) [MIM:268000]: A retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. {ECO:0000269|PubMed:19268277}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.124

Intolerance Scores

LoFtool: 0.987
RVIS EVS: 1.14
RVIS percentile EVS: 92.3

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.137

Gene Damage Prediction

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