ClinVar Miner

Submissions for variant NM_000503.6(EYA1):c.1276G>A (p.Gly426Ser) (rs121909199)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000309264 SCV000474831 likely benign Otofaciocervical syndrome 1 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000367199 SCV000474832 likely benign Branchiootorenal Spectrum Disorders 2016-06-14 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000606853 SCV000731974 uncertain significance not specified 2017-09-25 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Gly426Ser (c.1276G>A) variant in EYA1 has been reported in one Japanese individual with c onductive hearing loss with additional clinical features of branchio-oto-renal s yndrome (Azuma 2000), and parental testing confirmed de novo occurrence of the v ariant in the individual. This variant has also been identified in 0.18% (33/188 60) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http:/ /; dbSNP rs121909199); however this frequency is not hi gh enough to rule out a pathogenic role. The variant is also listed in ClinVar ( Variant ID 22977). Computational prediction tools and conservation analysis sugg est the variant may impact the protein. However, several in vitro functional stu dies provide conflicting data on the impact of the variant to normal protein fun ction (Buller 2001, Mutsuddi 2005, Rayapureddi 2006, Zou 2008, Li 2010, Ahmed 20 12, Patrick 2013, Musharraf 2014). It should be noted that in vitro studies may not accurately reflect biological function. In summary, while there is some sus picion for a pathogenic role, the clinical significance of the p.Gly426Ser varia nt is uncertain.
GeneDx RCV000657911 SCV000779677 uncertain significance not provided 2018-05-21 criteria provided, single submitter clinical testing The G426S variant has been published previously as an apparently de novo variant in a patient with BOR syndrome (Azuma et al., 2000). However, the variant is observed in 33/18860 (0.175%) alleles from individuals of East Asian background in large population cohorts (Lek et al., 2016). G426S is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. However, functional studies for this variant disagree on its effect. Some studies indicate G426S or its equivalent homologs reduce transcription level, affect otic development, and reduce interaction with Sox2 (Mutsuddi et al., 2005; Li et al., 2010; Zou et al., 2008). However, other studies have indicated G426S does not differ from wild-type (Ozaki et al., 2002; Musharraf et al., 2014). In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
OMIM RCV000008400 SCV000028608 pathogenic Branchiootorenal syndrome with cataract 2000-02-12 no assertion criteria provided literature only
Pediatric Nephrology (Iijima Lab),Kobe University Graduate School of Medicine RCV000496093 SCV000584168 benign Melnick-Fraser syndrome 2017-07-27 no assertion criteria provided clinical testing Two cases without BOR syndrome possessed this variant. We conclude this is benign.

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