ClinVar Miner

Submissions for variant NM_206933.4(USH2A):c.821G>A (p.Arg274Gln)

gnomAD frequency: 0.00003  dbSNP: rs727504721
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000156012 SCV000205724 uncertain significance not specified 2013-09-08 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The Arg274Gln varia nt in USH2A has not been reported in individuals with hearing loss or in large p opulation studies. The arginine (Arg) residue at position 274 is not well conser ved across species with cat and shrew having a glutamine (Gln) at that position. However, computational data (SIFT, PolyPhen2, AlignGVGD) provide conflicting pr edictions on the impact of the variant. In summary, the clinical significance of this variant cannot be determined with certainty; however based upon the conser vation data, we would lean towards a more likely benign role.
Counsyl RCV000673498 SCV000798706 uncertain significance Usher syndrome type 2A; Retinitis pigmentosa 39 2018-03-20 criteria provided, single submitter clinical testing
GeneDx RCV001731487 SCV001982230 uncertain significance not provided 2021-08-31 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27460420)
Invitae RCV001731487 SCV003283600 likely pathogenic not provided 2023-11-27 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 274 of the USH2A protein (p.Arg274Gln). This variant is present in population databases (rs727504721, gnomAD 0.006%). This missense change has been observed in individual(s) with inherited retinal dystrophy and/or Usher syndrome (PMID: 27460420, 34948090, 36460718; Invitae). ClinVar contains an entry for this variant (Variation ID: 179225). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant disrupts the p.Arg274 amino acid residue in USH2A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28041643; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Baylor Genetics RCV003462061 SCV004208317 likely pathogenic Retinitis pigmentosa 39 2023-08-23 criteria provided, single submitter clinical testing
Natera, Inc. RCV001831971 SCV002094012 uncertain significance Usher syndrome type 2A 2020-10-14 no assertion criteria provided clinical testing

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