ClinVar Miner

Submissions for variant NM_206933.3(USH2A):c.12284G>A (p.Gly4095Asp) (rs759898765)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000435312 SCV000515237 likely pathogenic not provided 2016-12-23 criteria provided, single submitter clinical testing The G4095D variant in the USH2A gene has been reported previously in two individuals with autosomal recessive Usher syndrome who also harbored second pathogenic variant in USH2A (Krawitz et al., 2014; Bonnet et al., 2016). The G4095D variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G4095D 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. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The G4095D variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Blueprint Genetics RCV001073281 SCV001238817 likely pathogenic Retinal dystrophy 2018-10-15 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000435312 SCV001246245 pathogenic not provided 2018-04-01 criteria provided, single submitter clinical testing
Invitae RCV000435312 SCV001374868 pathogenic not provided 2019-09-10 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 4095 of the USH2A protein (p.Gly4095Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is present in population databases (rs759898765, ExAC 0.001%). This variant has been observed in individuals affected with clinical features of Usher syndrome or retinitis pigmentosa (PMID: 25333064, 27460420, Invitae). ClinVar contains an entry for this variant (Variation ID: 378847). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Gly4095 amino acid residue in USH2A. Other variant(s) that disrupt this residue have been observed in individuals with USH2A-related conditions (PMID: 27460420), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

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