ClinVar Miner

Submissions for variant NM_206933.3(USH2A):c.9871G>A (p.Gly3291Ser) (rs138543813)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000665320 SCV000789420 uncertain significance Usher syndrome, type 2A; Retinitis pigmentosa 39 2017-01-31 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000825851 SCV000967335 likely benign not specified 2018-04-03 criteria provided, single submitter clinical testing The p.Gly3291Ser variant has been previously reported in one individual with Ush er syndrome; however the variant reported on the other allele (p.Tyr1992Cys) is classified as benign based on its frequency (Krawitz 2014). The p.Gly3291Ser var iant has been identified in 0.05% (59/126516) European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1385438 13). Although this variant has been seen in the general population, its frequen cy is not high enough to rule out a pathogenic role. Computational prediction to ols and conservation analyses suggest that this variant may not impact the prote in, and at least one mammal (shrew) has a Serine at this residue as do other low er species (birds, reptiles, fish). In summary, the clinical significance of the p.Gly3291Ser variant is likely benign. ACMG/AMP Criteria applied: BP4_Strong.
Invitae RCV001058364 SCV001222926 uncertain significance not provided 2019-12-17 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 3291 of the USH2A protein (p.Gly3291Ser). The glycine residue is moderately conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs138543813, ExAC 0.04%). This variant has been observed in an individual affected with Usher syndrome (PMID: 25333064). ClinVar contains an entry for this variant (Variation ID: 550545). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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