Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000190582 | SCV000245606 | likely pathogenic | Autosomal dominant nonsyndromic hearing loss 10 | 2014-07-02 | criteria provided, single submitter | clinical testing | 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. |
| Invitae | RCV001378781 | SCV001576434 | likely pathogenic | Dilated cardiomyopathy 1J | 2023-12-11 | criteria provided, single submitter | clinical testing | 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. |
| Ambry Genetics | RCV002399708 | SCV002711295 | likely pathogenic | Cardiovascular phenotype | 2021-09-20 | criteria provided, single submitter | clinical testing | 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. |
| Prevention |
RCV003401039 | SCV004103465 | likely pathogenic | EYA4-related condition | 2022-08-18 | criteria provided, single submitter | clinical testing | 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. |