ClinVar Miner

Submissions for variant NM_206933.4(USH2A):c.2332G>T (p.Asp778Tyr) (rs142898216)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000155332 SCV000205018 uncertain significance not specified 2014-11-07 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Asp778Tyr variant in USH2A has been reported in 1 Spanish individual with Usher syndrome who also carried a known pathogenic variant (Aller 2006). This variant has been identified in 0.05% (2/4406) of African American chromosomes by the NHLBI Exome Sequencing Project (; dbSNP rs142898216); howev er this frequency is not high enough to rule out a pathogenic role. Computationa l prediction tools suggest that the p.Asp778Tyr variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical signi ficance of the p.Asp778Tyr variant is uncertain.
Invitae RCV001051381 SCV001215533 pathogenic not provided 2020-08-26 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with tyrosine at codon 778 of the USH2A protein (p.Asp778Tyr). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and tyrosine. This variant is present in population databases (rs142898216, ExAC 0.08%). This variant has been observed in individual(s) with Usher syndrome or non-syndromic retinal disease (PMID: 17085681, 25649381, 26969326, Invitae). 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: 178583). 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. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV001073261 SCV001238797 pathogenic Retinal dystrophy 2018-09-26 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV001051381 SCV001248857 pathogenic not provided 2017-05-01 criteria provided, single submitter clinical testing
GeneDx RCV001051381 SCV001802507 uncertain significance not provided 2021-04-06 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31904091, 31736247, 17085681, 26969326, 32637036, 25649381)

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