ClinVar Miner

Submissions for variant NM_206933.3(USH2A):c.14426C>T (p.Thr4809Ile) (rs770553471)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000657876 SCV000704436 uncertain significance not provided 2016-12-19 criteria provided, single submitter clinical testing
GeneDx RCV000657876 SCV000779637 likely pathogenic not provided 2018-12-07 criteria provided, single submitter clinical testing The T4809I variant in the USH2A gene has been reported previously in individuals with Usher syndrome type II who also harbored an additional variant in the USH2A gene, although parental studies were not performed to confirm the phase of these variants in all of these studies (Ebermann et al., 2009; Bonnet et al., 2011; Baux et al., 2014; Lenassi et al., 2015; Bonnet et al., 2016; Carss et al., 2017). The T4809I variant is observed in 1/15,304 (0.0065%) alleles from individuals of African background and 2/246,160 global alleles in large population cohorts (Lek et al., 2016). The T4809I variant 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. We interpret T4809I as a likely pathogenic variant.
Counsyl RCV000674502 SCV000799849 likely pathogenic Usher syndrome, type 2A; Retinitis pigmentosa 39 2018-05-10 criteria provided, single submitter clinical testing
Invitae RCV000657876 SCV001199938 likely pathogenic not provided 2019-12-20 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 4809 of the USH2A protein (p.Thr4809Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs770553471, ExAC 0.01%). This variant has been observed in several individuals with Usher syndrome and an individual with retinitis pigmentosa (PMID: 18665195, 21569298, 25649381, 27460420, 24944099). ClinVar contains an entry for this variant (Variation ID: 438016). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
NIHR Bioresource Rare Diseases, University of Cambridge RCV000504707 SCV000598792 likely pathogenic Usher syndrome 2015-01-01 no assertion criteria provided research

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