ClinVar Genomic variation as it relates to human health
NM_000503.6(EYA1):c.1276G>A (p.Gly426Ser)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Uncertain significance(2); Likely benign(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000503.6(EYA1):c.1276G>A (p.Gly426Ser)
Variation ID: 7938 Accession: VCV000007938.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 8q13.3 8: 71216776 (GRCh38) [ NCBI UCSC ] 8: 72129011 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Dec 7, 2014 Dec 17, 2022 Dec 2, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000503.6:c.1276G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000494.2:p.Gly426Ser missense NM_001288574.2:c.1258G>A NP_001275503.1:p.Gly420Ser missense NM_001288575.2:c.910G>A NP_001275504.1:p.Gly304Ser missense NM_001370333.1:c.1363G>A NP_001357262.1:p.Gly455Ser missense NM_001370334.1:c.1276G>A NP_001357263.1:p.Gly426Ser missense NM_001370335.1:c.1276G>A NP_001357264.1:p.Gly426Ser missense NM_001370336.1:c.1255G>A NP_001357265.1:p.Gly419Ser missense NM_172058.4:c.1276G>A NP_742055.1:p.Gly426Ser missense NM_172059.5:c.1258G>A NP_742056.2:p.Gly420Ser missense NC_000008.11:g.71216776C>T NC_000008.10:g.72129011C>T NG_011735.3:g.336355G>A Q99502:p.Gly426Ser - Protein change
- G426S, G304S, G455S, G419S, G420S
- Other names
- G393S
- Canonical SPDI
- NC_000008.11:71216775:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- unknown functional consequence
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00006
Exome Aggregation Consortium (ExAC) 0.00014
The Genome Aggregation Database (gnomAD), exomes 0.00014
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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EYA1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
529 | 566 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
no assertion criteria provided
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Feb 12, 2000 | RCV000008400.3 | |
Likely benign (1) |
criteria provided, single submitter
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Apr 28, 2017 | RCV000309264.5 | |
Likely benign (1) |
criteria provided, single submitter
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Apr 28, 2017 | RCV000367199.5 | |
Benign (1) |
no assertion criteria provided
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Jul 27, 2017 | RCV000496093.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Sep 25, 2017 | RCV000606853.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 2, 2022 | RCV000657911.3 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain significance
(Sep 25, 2017)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000731974.1
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Comment:
Variant classified as Uncertain Significance - Favor Pathogenic. The p.Gly426Ser (c.1276G>A) variant in EYA1 has been reported in one Japanese individual with c onductive hearing … (more)
Variant classified as Uncertain Significance - Favor Pathogenic. The p.Gly426Ser (c.1276G>A) variant in EYA1 has been reported in one Japanese individual with c onductive hearing loss with additional clinical features of branchio-oto-renal s yndrome (Azuma 2000), and parental testing confirmed de novo occurrence of the v ariant in the individual. This variant has also been identified in 0.18% (33/188 60) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http:/ /gnomad.broadinstitute.org; dbSNP rs121909199); however this frequency is not hi gh enough to rule out a pathogenic role. The variant is also listed in ClinVar ( Variant ID 22977). Computational prediction tools and conservation analysis sugg est the variant may impact the protein. However, several in vitro functional stu dies provide conflicting data on the impact of the variant to normal protein fun ction (Buller 2001, Mutsuddi 2005, Rayapureddi 2006, Zou 2008, Li 2010, Ahmed 20 12, Patrick 2013, Musharraf 2014). It should be noted that in vitro studies may not accurately reflect biological function. In summary, while there is some sus picion for a pathogenic role, the clinical significance of the p.Gly426Ser varia nt is uncertain. (less)
Number of individuals with the variant: 1
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Likely benign
(Apr 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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Branchiootic syndrome
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000474832.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
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Likely benign
(Apr 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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Otofaciocervical syndrome 1
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000474831.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
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Uncertain significance
(Dec 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000779677.3
First in ClinVar: Jul 09, 2018 Last updated: Dec 17, 2022 |
Comment:
Functional studies for this variant disagree on its effect; some indicate G426S or equivalent homologs reduce transcription level, affect optic development, and reduce interaction with … (more)
Functional studies for this variant disagree on its effect; some indicate G426S or equivalent homologs reduce transcription level, affect optic development, and reduce interaction with Sox2 (Mutsuddi et al., 2005; Li et al., 2010; Zou et al., 2008), while others indicate G426S does not differ from wild-type (Ozaki et al., 2002; Musharraf et al., 2014); This variant is associated with the following publications: (PMID: 30221713, 29043394, 16797546, 11734542, 23435380, 10655545, 22340499, 24752894, 18678597, 19951260, 11950062, 24489909, 15802522, 35114279, 34868248) (less)
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Pathogenic
(Feb 12, 2000)
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no assertion criteria provided
Method: literature only
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BRANCHIOOTORENAL SYNDROME WITH CATARACT
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000028608.2
First in ClinVar: Apr 04, 2013 Last updated: Dec 07, 2014 |
Comment on evidence:
Azuma et al. (2000) identified a gly393-to-ser mutation in an 8-year-old boy who first presented at their hospital with nystagmus and systemic edema at 20 … (more)
Azuma et al. (2000) identified a gly393-to-ser mutation in an 8-year-old boy who first presented at their hospital with nystagmus and systemic edema at 20 days of age. Examinations revealed bilateral nuclear-type congenital cataracts with a normal fundus, and multicystic dysplasia in his right kidney, which did not function and caused hypocalcemia. The cataracts were operated on at 1 month of age and the right kidney was removed at 2 months. He was later found to have conductive deafness with the malleus anomaly. He also had cervical fistula that occluded spontaneously. Except for the cataracts, the clinical findings were considered typical of BOR syndrome (BOR1; 113650). (less)
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Benign
(Jul 27, 2017)
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no assertion criteria provided
Method: clinical testing
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Branchiootorenal syndrome 1
(Autosomal dominant inheritance)
Affected status: no
Allele origin:
germline
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Pediatric Nephrology (Iijima Lab), Kobe University Graduate School of Medicine
Accession: SCV000584168.1
First in ClinVar: Aug 04, 2017 Last updated: Aug 04, 2017 |
Comment:
Two cases without BOR syndrome possessed this variant. We conclude this is benign.
Age: 10-19 years
Sex: male
Ethnicity/Population group: Japanese
Testing laboratory: Iijima Lab
Date variant was reported to submitter: 2017-05-22
Testing laboratory interpretation: Benign
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Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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unknown functional consequence
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Pediatric Nephrology (Iijima Lab), Kobe University Graduate School of Medicine
Accession: SCV000584168.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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BOR-syndrome-associated Eya1 mutations lead to enhanced proteasomal degradation of Eya1 protein. | Musharraf A | PloS one | 2014 | PMID: 24489909 |
Structure-function analyses of the human SIX1-EYA2 complex reveal insights into metastasis and BOR syndrome. | Patrick AN | Nature structural & molecular biology | 2013 | PMID: 23435380 |
Eya1-Six1 interaction is sufficient to induce hair cell fate in the cochlea by activating Atoh1 expression in cooperation with Sox2. | Ahmed M | Developmental cell | 2012 | PMID: 22340499 |
EYA1 mutations associated with the branchio-oto-renal syndrome result in defective otic development in Xenopus laevis. | Li Y | Biology of the cell | 2010 | PMID: 19951260 |
Eya1 gene dosage critically affects the development of sensory epithelia in the mammalian inner ear. | Zou D | Human molecular genetics | 2008 | PMID: 18678597 |
Branchio-oto-renal syndrome associated mutations in Eyes Absent 1 result in loss of phosphatase activity. | Rayapureddi JP | FEBS letters | 2006 | PMID: 16797546 |
Using Drosophila to decipher how mutations associated with human branchio-oto-renal syndrome and optical defects compromise the protein tyrosine phosphatase and transcriptional functions of eyes absent. | Mutsuddi M | Genetics | 2005 | PMID: 15802522 |
Molecular effects of Eya1 domain mutations causing organ defects in BOR syndrome. | Buller C | Human molecular genetics | 2001 | PMID: 11734542 |
Mutations of a human homologue of the Drosophila eyes absent gene (EYA1) detected in patients with congenital cataracts and ocular anterior segment anomalies. | Azuma N | Human molecular genetics | 2000 | PMID: 10655545 |
Text-mined citations for rs121909199 ...
HelpRecord last updated Feb 14, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.