Submissions for variant NM_000503.6(EYA1):c.1460C>T (p.Ser487Leu)

gnomAD frequency: 0.00069  dbSNP: rs139717960

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000214933	SCV000271773	likely benign	not specified	2019-04-12	criteria provided, single submitter	clinical testing	The p.Ser487Leu variant in EYA1 is classified as likely benign because it is present in 0.13% (177/129002) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has been reported in 1 individual with Branchio-oto-renal syndrome, 2 individuals with hearing loss, and 4 individuals with vesicouretal reflux/CAKUT (Chang 2004, Neveling 2013, Hwang 2014, Nicolaou 2016). It has also been identified in 1 individual with ear abnormalities and hypoplastic kidneys who also had a 2q23 microdeletion and a de novo pathogenic variant in the CHD7 gene; the p.Ser487Leu variant segregated in the father with branchial cyst and duplication of renal collecting system (Badilla-Porras 2012). This variant has been reported by our laboratory in 2 unrelated Caucasian individuals with sensorineural hearing loss due to alternate genetic etiologies as well as in an unaffected parent. In summary, the frequency data and identification of this variant in individuals with an alternate genetic etiology and unaffected parent support a likely benign classification, despite the reports in the literature. ACMG/AMP Criteria applied: BA1, BS2_Supporting, BP5, PS4_Supporting.
Illumina Laboratory Services, Illumina	RCV000401819	SCV000474827	likely benign	Otofaciocervical syndrome 1	2017-04-27	criteria provided, single submitter	clinical testing	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.
Illumina Laboratory Services, Illumina	RCV000289230	SCV000474828	likely benign	Branchiootic syndrome 1	2017-04-27	criteria provided, single submitter	clinical testing	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.
CeGaT Center for Human Genetics Tuebingen	RCV000488133	SCV000575559	benign	not provided	2022-09-01	criteria provided, single submitter	clinical testing	EYA1: BS1, BS2
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000488133	SCV000610049	likely benign	not provided	2017-05-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000488133	SCV000728396	likely benign	not provided	2020-08-17	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24429398, 18220287, 15146463, 22995991, 24123792, 26489027, 9361030, 29966037)
Mendelics	RCV000401819	SCV001137643	benign	Otofaciocervical syndrome 1	2023-08-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001401859	SCV001603693	likely benign	Melnick-Fraser syndrome	2023-12-17	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003401130	SCV004105212	uncertain significance	EYA1-related disorder	2023-05-22	criteria provided, single submitter	clinical testing	The EYA1 c.1460C>T variant is predicted to result in the amino acid substitution p.Ser487Leu. This variant has been reported in at least one individual with branchiootorenal (BOR) syndrome (referred to as c.1361T>C, p.Ser454Leu, Chang et al. 2004. PubMed ID: 15146463) and another individual with progressive hearing loss (Table S13, Neveling et al. 2013. PubMed ID: 24123792). It has been interpreted as non-pathogenic for congenital anomalies of the kidney and urinary tract (CAKUT, Table S2, Hwang et al. 2014. PubMed ID: 24429398;) and uncertain significance for BOR syndrome (Table S5, Nicolaou et al. 2016. PubMed ID: 26489027). This variant has been reported 212 times among ~283,000 alleles (~0.08%) in a large population database (https://gnomad.broadinstitute.org/variant/chr8-72127864-G-A), and has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/228678/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Dept. Genetics and Cancer, Menzies Institute for Medical Research, University of Tasmania	RCV001775005	SCV001573172	benign	Developmental cataract	2021-05-01	no assertion criteria provided	research