ClinVar Miner

Submissions for variant NM_206933.3(USH2A):c.908G>A (p.Arg303His) (rs371777049)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000276147 SCV000337027 pathogenic not provided 2015-12-01 criteria provided, single submitter clinical testing
Invitae RCV000276147 SCV001224324 pathogenic not provided 2020-10-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 303 of the USH2A protein (p.Arg303His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs371777049, ExAC 0.008%). This variant has been observed in individual(s) with Usher syndrome and retinitis pigmentosa (PMID: 19881469, 28157192, 25342620). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 284411). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Deleterious; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0. The histidine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Arg303 amino acid residue in USH2A. Other variant(s) that disrupt this residue have been observed in individuals with USH2A-related conditions (PMID:28157192, 14970843), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV001074790 SCV001240386 pathogenic Retinal dystrophy 2019-07-02 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000276147 SCV001250065 pathogenic not provided 2020-11-01 criteria provided, single submitter clinical testing
GeneDx RCV000276147 SCV001766817 pathogenic not provided 2020-10-30 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 24944099, 25342620, 22004887, 21569298, 28157192, 31766479, 30872814, 19881469)
Counsyl RCV000666542 SCV000790848 likely pathogenic Retinitis pigmentosa 39 2017-04-12 no assertion criteria provided clinical testing
Center for Statistical Genetics, Columbia University RCV000754554 SCV000853292 pathogenic Hearing impairment 2018-10-08 no assertion criteria provided research
University of Washington Center for Mendelian Genomics, University of Washington RCV000754554 SCV001439132 likely pathogenic Hearing impairment no assertion criteria provided research

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