Submissions for variant NM_000503.6(EYA1):c.1319G>A (p.Arg440Gln)

dbSNP: rs121909196

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000844628	SCV000065081	pathogenic	Rare genetic deafness	2011-05-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002228019	SCV000815067	pathogenic	Melnick-Fraser syndrome	2024-12-23	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 440 of the EYA1 protein (p.Arg440Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with branchiootorenal syndrome (PMID: 10464653, 15146463, 18220287, 21280147, 28832562). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this EYA1 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 10,567 individuals referred to our laboratory for EYA1 testing. This variant is also known as c.1220G>A (p.Arg407Gln). ClinVar contains an entry for this variant (Variation ID: 7935). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt EYA1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects EYA1 function (PMID: 19951260, 24489909). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
MGZ Medical Genetics Center	RCV002288475	SCV002579950	likely pathogenic	Branchiootic syndrome 1	2022-08-02	criteria provided, single submitter	clinical testing
Center for Statistical Genetics, Columbia University	RCV000008397	SCV005415635	pathogenic	Branchiootorenal syndrome 1	2024-11-08	criteria provided, single submitter	research
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004795383	SCV005418131	pathogenic	Branchiootic syndrome 1; Branchiootorenal syndrome 1; Otofaciocervical syndrome 1		criteria provided, single submitter	clinical testing	PM2+PS4+PP1_Strong+PM1+PS3_Moderate+PP3
OMIM	RCV000008397	SCV000028605	pathogenic	Branchiootorenal syndrome 1	1997-01-01	no assertion criteria provided	literature only
Yale Center for Mendelian Genomics, Yale University	RCV001849260	SCV002106556	pathogenic	Branchiooculofacial syndrome	2019-01-17	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004739295	SCV005360187	pathogenic	EYA1-related disorder	2024-09-03	no assertion criteria provided	clinical testing	The EYA1 c.1319G>A variant is predicted to result in the amino acid substitution p.Arg440Gln. This variant is also referred to as c.1220G>A or R407Q in the literature, corresponding to NM_172060. It has been reported in individuals with branchio-oto-renal syndrome (see, for example, Kumar et al. 1997. PubMed ID: 10464653; Orten et al. 2008. PubMed ID: 18220287; Mann et al. 2019. PubMed ID: 30655312), including some in whom it was reported de novo (Masuda et al. 2022. PubMed ID: 35046468; Cho et al. 2024. PubMed ID: 39125727). An in vivo experimental study indicated this variant affected development of the otic vesicle and vestibulocochlear nerve in Xenopus laevis embryos (referred to as R435Q, Li et al. 2010. PubMed ID: 19951260). An additional study indicated this variant protein was able to translocate into the nucleus with similar efficiency to wild type (Musharraf et al. 2014. PubMed ID: 24489909). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.