EYA1

Chr 8AD

EYA transcriptional coactivator and phosphatase 1

Also known as: BOP, BOR, BOS1, OFC1, OTFCS

NCBI Gene: 2138 ENSG00000104313 UniProt: Q99502 OMIM: 601653

The EYA1 protein functions as both a tyrosine phosphatase that dephosphorylates histone H2AX to promote DNA repair and as a transcriptional coactivator for SIX family proteins during organogenesis. Mutations cause branchiootorenal syndrome, branchiootic syndrome, and anterior segment eye anomalies with or without cataracts, affecting development of the kidneys, ears, branchial arches, and eyes. The gene follows autosomal dominant inheritance and is highly constrained against loss-of-function variants.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the eyes absent (EYA) family of proteins. The encoded protein may play a role in the developing kidney, branchial arches, eye, and ear. Mutations of this gene have been associated with branchiootorenal dysplasia syndrome, branchiootic syndrome, and sporadic cases of congenital cataracts and ocular anterior segment anomalies. A similar protein in mice can act as a transcriptional activator. Alternatively spliced transcript variants have been identified for this gene. [provided by RefSeq, Dec 2013]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.334 OMIM phenotypes

Clinical Summary— EYA1

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Gene-Disease Validity (ClinGen)

branchio-oto-renal syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.95). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

208 unique Pathogenic / Likely Pathogenic· 277 VUS of 736 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — EYA1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.33LOEUF

pLI 0.946

Z-score 4.60

OE 0.17 (0.09–0.33)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

1.02Z-score

OE missense 0.84 (0.76–0.93)

273 obs / 324.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.17 (0.09–0.33)

0≤0.351.4

Missense OE?0.84 (0.76–0.93)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 6 / 35.7Missense obs/exp: 273 / 324.7Syn Z: 0.08

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveEYA1-related branchiootorenal syndromeLOFAD

This gene — mechanism propensity

0.3594th %ile

GOF

0.2397th %ile

LOF

0.76top 10%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · 82% of P/LP variants are LoF · LOEUF 0.33 · ClinGen HI: Sufficient evidence for dosage pathogenicity

DN1 literature citation

GOF1 literature citation

Literature Evidence

DNThese studies lend support to the hypothesis that dominant-negative effects of EYA1 mutations may have a role in the pathogenesis of BOR.1

GOFWesuggest that the pathogenesis of BOR syndrome involves a compo-nent of dominant-negative gain-of-function effects, in addition to the previously reported haploinsuficiency model.2

LOFA novel mutation in EYA1 in a Chinese family with Branchio-oto-renal syndrome3

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

ClinVar Variant Classifications

736 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic132

Likely Pathogenic76

VUS277

Likely Benign142

Benign58

Conflicting41

132

Pathogenic

Likely Pathogenic

277

VUS

142

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	113	6	13	0	132
Likely Pathogenic	57	14	5	0	76
VUS	5	197	65	10	277
Likely Benign	1	17	78	46	142
Benign	0	2	49	7	58
Conflicting	—				41
Total	176	236	210	63	726

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

41 pathogenic / likely-pathogenic (of 44) ClinVar copy-number / structural variants overlap EYA1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →