| Gene/Disease Pair: | EYA1 : branchio-oto-renal syndrome |
| HGNC:3519 | MONDO_0007029 | |
| Mode of Inheritance: | Autosomal dominant inheritance (HP:0000006) |
| Expert Panel: | Hearing Loss EP |
| SOP: | Gene Clinical Validity Standard Operating Procedures (SOP), Version 5 |
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Genetic Evidence
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Case-Level Data
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Evidence Type | Case Information Type | Guidelines | Points | PMIDs/Notes | ||||||
| Default | Range | Max | Total | Counted | ||||||||
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Variant Evidence
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Autosomal Dominant or X-linked Disorder | Variant is de novo | 2 | 0-3 | 12 |
6
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6 |
Stockley TL et al. 2009 Mar (PMID:19206155);
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| Proband with predicted or proven null variant | 1.5 | 0-2 | 10 | 6 | 6 |
Orten DJ et al. 2008 Apr (PMID:18220287);
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| Proband with other variant type with some evidence of gene impact | 0.5 | 0-1.5 | 7 |
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| Autosomal Recessive Disease | Two variants in trans and at least one de novo or a predicted/proven null variant | 2 | 0-3 | 12 |
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| Two variants (not predicted/proven null) with some evidence of gene impact in trans | 1 | 0-1.5 | ||||||||||
| Segregation Evidence | Evidence of segregation in one or more families | Sequencing Method | 0-3 | 3 |
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| Total LOD Score | Canditate Gene Sequencing | Exome/Genome or all genes sequenced in linkage region | ||||||||||
| 2-2.99 | 0.5 | 1 | ||||||||||
| 3-4.99 | 1 | 2 | ||||||||||
| ≥5 | 1.5 | 3 | ||||||||||
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Case-Control Data
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Case-Control Study Type | Case-Control Quality Criteria | Guidelines | Points | PMIDs/Notes | |||||||
| Points/Study | Max | Total | Counted | |||||||||
| Single Variant Analysis | 1. Variant Detection Methodology 2. Power 3. Bias and confounding 4. Statistical Significance |
0-6 | 12 |
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| Aggregate Variant Analysis | 0-6 |
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| Total Genetic Evidence Points (Maximum 12) | 12 |
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Experimental Evidence
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Evidence Category | Evidence Type | Guidelines | Points | PMIDs/Notes | |||||||
| Default | Range | Max | Total | Counted | ||||||||
| Function | Biochemical Function | 0.5 | 0 - 2 | 2 |
0.5
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2 |
Li X et al. 2003 Nov 20 (PMID:14628042);
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| Protein Interaction | 0.5 | 0 - 2 | 1.5 |
Li X et al. 2003 Nov 20 (PMID:14628042); Buller C et al. 2001 Nov 15 (PMID:11734542);
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| Expression | 0.5 | 0 - 2 | ||||||||||
| Functional Alteration | Patient cells | 1 | 0 - 2 | 2 |
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0.5 | ||||||
| Non-patient cells | 0.5 | 0 - 1 | 0.5 |
Buller C et al. 2001 Nov 15 (PMID:11734542);
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| Models | Non-human model organism | 2 | 0 - 4 | 4 | 3 | 3.5 |
Johnson KR et al. 1999 Apr (PMID:10072433); Li Y et al. 2010 Feb 17 (PMID:19951260);
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| Cell culture model | 1 | 0 - 2 | ||||||||||
| Rescue | Rescue in human | 2 | 0 - 4 |
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| Rescue in non-human model organism | 2 | 0 - 4 |
0.5
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Li Y et al. 2010 Feb 17 (PMID:19951260);
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| Rescue in cell culture model | 1 | 0 - 2 | ||||||||||
| Rescue in patient cells | 1 | 0 - 2 | ||||||||||
| Total Experimental Evidence Points (Maximum 6) | 6 |
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| Assertion criteria | Genetic Evidence (0-12 points) | Experimental Evidence
(0-6 points) |
Total Points
(0-18) |
Replication Over Time (Y/N) | ||
| Description | Case-level, family segregation, or case-control data that support the gene-disease association | Gene-level experimental evidence that support the gene-disease association | Sum of Genetic & Experimental
Evidence |
> 2 pubs w/ convincing evidence over time (>3 yrs) | ||
| Assigned Points | 12 | 6 | 18 | YES | ||
| CALCULATED CLASSIFICATION | LIMITED | 1-6 | ||||
| MODERATE | 7-11 | |||||
| STRONG | 12-18 | |||||
| DEFINITIVE | 12-18 AND replication over time | |||||
| Valid contradictory evidence (Y/N)*
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| CALCULATED CLASSIFICATION (DATE) |
Definitive
08/30/2018
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| EXPERT CURATION (DATE) |
Definitive
08/30/2018
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| EVIDENCE SUMMARY |
The EYA1 gene has been associated with autosomal dominant Branchio-oto-renal syndrome using the ClinGen Clinical Validity Framework as of 10/17/17. This association was made using case-level data. Multiple missense, nonsense, frameshift and splice-site variants have been reported in humans. EYA1 was first associated with this disease in humans as early as 1997 (Abdelhak et al.). Nine probands, familial and de novo, were scored for this curation (9020840, 18220287, 19206155). More evidence is available in the literature, but the maximum score for genetic evidence and experimental evidence has been reached. This gene-disease association is supported by a spontaneous mouse model, a Xenopus model and a rescue in Xenopus oocytes (10072433, 19951260). In summary, EYA1 is definitively associated with autosomal dominant Branchio-oto-renal syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hearing Loss Working Group on 11/21/17.
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