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NM_004100.5(EYA4):c.1739-1G>A AND Cardiovascular phenotype

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Sep 20, 2021
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV002399708.9

Allele description [Variation Report for NM_004100.5(EYA4):c.1739-1G>A]

NM_004100.5(EYA4):c.1739-1G>A

Genes:
EYA4:EYA transcriptional coactivator and phosphatase 4 [Gene - OMIM - HGNC]
TARID:TCF21 antisense RNA inducing promoter demethylation [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
6q23.2
Genomic location:
Preferred name:
NM_004100.5(EYA4):c.1739-1G>A
HGVS:
  • NC_000006.12:g.133525153G>A
  • NG_011596.2:g.288797G>A
  • NM_001301012.2:c.1677+38G>A
  • NM_001301013.2:c.1757-1G>A
  • NM_001370458.1:c.1770+38G>A
  • NM_001370459.1:c.1595-1G>A
  • NM_004100.5:c.1739-1G>AMANE SELECT
  • NM_172103.4:c.1670-1G>A
  • NM_172105.4:c.1839+38G>A
  • LRG_418t1:c.1739-1G>A
  • LRG_418:g.288797G>A
  • NC_000006.11:g.133846291G>A
  • NM_004100.4:c.1739-1G>A
Links:
dbSNP: rs797045088
NCBI 1000 Genomes Browser:
rs797045088
Molecular consequence:
  • NM_001301012.2:c.1677+38G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001370458.1:c.1770+38G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_172105.4:c.1839+38G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001301013.2:c.1757-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001370459.1:c.1595-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_004100.5:c.1739-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_172103.4:c.1670-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]

Condition(s)

Name:
Cardiovascular phenotype
Identifiers:
MedGen: CN230736

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002711295Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Likely pathogenic
(Sep 20, 2021) 		germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Interpreting secondary cardiac disease variants in an exome cohort.

Ng D, Johnston JJ, Teer JK, Singh LN, Peller LC, Wynter JS, Lewis KL, Cooper DN, Stenson PD, Mullikin JC, Biesecker LG; NIH Intramural Sequencing Center (NISC) Comparative Sequencing Program..

Circ Cardiovasc Genet. 2013 Aug;6(4):337-46. doi: 10.1161/CIRCGENETICS.113.000039. Epub 2013 Jul 16.

PubMed [citation]
PMID:
23861362
PMCID:
PMC3887521

A Comparison of Whole Genome Sequencing to Multigene Panel Testing in Hypertrophic Cardiomyopathy Patients.

Cirino AL, Lakdawala NK, McDonough B, Conner L, Adler D, Weinfeld M, O'Gara P, Rehm HL, Machini K, Lebo M, Blout C, Green RC, MacRae CA, Seidman CE, Ho CY; MedSeq Project*..

Circ Cardiovasc Genet. 2017 Oct;10(5). doi:pii: e001768. 10.1161/CIRCGENETICS.117.001768.

PubMed [citation]
PMID:
29030401
PMCID:
PMC5683423

Details of each submission

From Ambry Genetics, SCV002711295.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jun 9, 2024