ClinVar Genomic variation as it relates to human health
NM_004100.5(EYA4):c.1739-1G>A
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_004100.5(EYA4):c.1739-1G>A
Variation ID: 208577 Accession: VCV000208577.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 6q23.2 6: 133525153 (GRCh38) [ NCBI UCSC ] 6: 133846291 (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 Sep 14, 2015 May 1, 2024 Dec 11, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004100.5:c.1739-1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice acceptor NM_001301012.2:c.1677+38G>A intron variant NM_001301013.2:c.1757-1G>A splice acceptor NM_001370458.1:c.1770+38G>A intron variant NM_001370459.1:c.1595-1G>A splice acceptor NM_172103.4:c.1670-1G>A splice acceptor NM_172105.4:c.1839+38G>A intron variant NC_000006.12:g.133525153G>A NC_000006.11:g.133846291G>A NG_011596.2:g.288797G>A LRG_418:g.288797G>A LRG_418t1:c.1739-1G>A - Protein change
- Other names
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- Canonical SPDI
- NC_000006.12:133525152:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
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
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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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EYA4 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
580 | 967 | |
TARID | - | - | GRCh38 | - | 377 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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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Likely pathogenic (1) |
criteria provided, single submitter
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Dec 11, 2023 | RCV001378781.11 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Sep 20, 2021 | RCV002399708.9 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Sep 4, 2015 | RCV004017475.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Aug 18, 2022 | RCV004528973.1 |
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
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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
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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
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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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Likely Pathogenic
(Sep 04, 2015)
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criteria provided, single submitter
Method: clinical testing
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Rare genetic deafness
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Study: CSER-MedSeq
Accession: SCV000245606.2 First in ClinVar: Sep 14, 2015 Last updated: Apr 20, 2024 |
Comment:
The c.1739-1G>A variant in EYA4 has not been reported in individuals with hearing loss or in large population studies. This variant occurs in the invariant … (more)
The c.1739-1G>A variant in EYA4 has not been reported in individuals with hearing loss or in large population studies. This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. This variant resides near exon 18 and a nonsense variant in this exon was shown to segregate with deafness in one family (Wayne 2001), providing further evidence that loss-of-function variants in or near this exon may lead to an abnormal or absent protein. In summary, although additional studies are required to fully establish its clinical significance, the c.1739-1G>A variant is likely pathogenic. (less)
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Likely pathogenic
(Aug 18, 2022)
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criteria provided, single submitter
Method: clinical testing
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EYA4-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004103465.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The EYA4 c.1739-1G>A variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. To our knowledge, this variant has not … (more)
The EYA4 c.1739-1G>A variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. To our knowledge, this variant has not been reported in the literature in a patient with hearing loss. This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Variants that disrupt the consensus splice acceptor site in EYA4 are expected to be pathogenic and this variant is interpreted as likely pathogenic by three different laboratories in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/208577/). This variant is interpreted as likely pathogenic. (less)
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Likely pathogenic
(Dec 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Dilated cardiomyopathy 1J
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001576434.4
First in ClinVar: May 10, 2021 Last updated: Feb 20, 2024 |
Comment:
This sequence change affects an acceptor splice site in intron 18 of the EYA4 gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more)
This sequence change affects an acceptor splice site in intron 18 of the EYA4 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in EYA4 are known to be pathogenic (PMID: 11159937, 25781927, 25963406). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with EYA4-related conditions. ClinVar contains an entry for this variant (Variation ID: 208577). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
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Likely pathogenic
(Sep 20, 2021)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002711295.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.1739-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 18 of the EYA4 gene. This variant has … (more)
The c.1739-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 18 of the EYA4 gene. This variant has been detected in an individual from a hypertrophic cardiomyopathy cohort who also had hearing loss. Audiology tracings in this individual were considered consistent with EYA4-related hearing loss (Cirino AL et al. Circ Cardiovasc Genet, 2017 Oct;10). This alteration has also been reported as a secondary cardiac variant in an exome cohort; however, clinical details were limited (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. This alteration occurs at the 3' terminus of the EYA4 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 9% (60 amino acids) of the protein. The exact functional effect of this alteration is unknown; however, the impacted region is critical for protein function (Ambry internal data). While loss of function of EYA4 has not been clearly established as a mechanism of disease for cardiomyopathy, loss of function has been established as a mechanism of disease for hearing loss. Based on the supporting evidence, this alteration is likely pathogenic for EYA4-related hearing loss; however, the association of this alteration with EYA4-related cardiomyopathy is unknown. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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A Comparison of Whole Genome Sequencing to Multigene Panel Testing in Hypertrophic Cardiomyopathy Patients. | Cirino AL | Circulation. Cardiovascular genetics | 2017 | PMID: 29030401 |
A novel EYA4 mutation causing hearing loss in a Chinese DFNA family and genotype-phenotype review of EYA4 in deafness. | Huang A | Journal of translational medicine | 2015 | PMID: 25963406 |
Evaluation of the contribution of the EYA4 and GRHL2 genes in Korean patients with autosomal dominant non-syndromic hearing loss. | Kim YR | PloS one | 2015 | PMID: 25781927 |
Interpreting secondary cardiac disease variants in an exome cohort. | Ng D | Circulation. Cardiovascular genetics | 2013 | PMID: 23861362 |
Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
Mutations in the transcriptional activator EYA4 cause late-onset deafness at the DFNA10 locus. | Wayne S | Human molecular genetics | 2001 | PMID: 11159937 |
Text-mined citations for rs797045088 ...
HelpRecord last updated May 19, 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.