Submissions for variant NM_000503.6(EYA1):c.865G>T (p.Asp289Tyr)

gnomAD frequency: 0.00011  dbSNP: rs201504674

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000595354	SCV000708067	uncertain significance	not provided	2017-04-26	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825755	SCV000967217	likely benign	not specified	2018-04-11	criteria provided, single submitter	clinical testing	The p.Asp289Tyr variant in EYA1 has been reported in 0.02% (30/126700) of Europe an chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadin stitute.org; dbSNP rs201504674). This frequency is too high to cause Branchio-ot o-renal syndrome, which has a prevalence of 1/40,000). Though the variant has be en reported in 1 German proband with renal abnormalities, this individual also h ad additional clinical features that are not consistent with BOR syndrome, and a microdeletion in 14q32 was identified, which is consistent with their phenotype s (Classen 2013). In summary, this variant is likely benign based on its frequen cy in the general population. ACMG/AMP Criteria applied: BS1.
Mendelics	RCV000988072	SCV001137644	uncertain significance	Otofaciocervical syndrome 1	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001160700	SCV001322521	benign	Branchiootic syndrome 1	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV000988072	SCV001322522	benign	Otofaciocervical syndrome 1	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center	RCV001375139	SCV001572100	uncertain significance	Hearing impairment	2021-04-12	criteria provided, single submitter	clinical testing	PP3_Supporting, BS2_Strong
GeneDx	RCV000595354	SCV002013244	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing	Identified in a patient with a renal abnormality in published literature; however, the variant was inherited from an unaffected parent, the individual's phenotype was not consistent with BOR syndrome, and additional genetic variants were identified (Classen et al., 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23552953)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001854090	SCV002175137	likely benign	Melnick-Fraser syndrome	2024-09-23	criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV001160700	SCV003839042	uncertain significance	Branchiootic syndrome 1	2022-10-21	criteria provided, single submitter	clinical testing	This EYA1 missense variant has been identified in an individual with complex phenotype including renal abnormality, and the individual harbored additional genetic variants that did not explain the renal phenotype. The variant (rs201504674) is rare (<0.1%) in a large population dataset (gnomAD: 40/282872 total alleles; 0.014%; no homozygotes), and has been reported in ClinVar (Variation ID 501623). Two bioinformatic tools queried predict that this substitution would be damaging, and the aspartic acid residue at this position is evolutionarily conserved across most of the species assessed. We consider the clinical significance of c.865G>T in EYA1 to be uncertain at this time.
Gharavi Laboratory, Columbia University	RCV000595354	SCV000920746	uncertain significance	not provided	2018-09-16	no assertion criteria provided	research