ClinVar Miner

Submissions for variant NM_206933.4(USH2A):c.12241C>T (p.Arg4081Trp)

gnomAD frequency: 0.00047  dbSNP: rs144783615
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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 RCV000217686 SCV000272887 uncertain significance not specified 2016-02-21 criteria provided, single submitter clinical testing The p.Arg4081Trp variant in USH2A has not been previously reported in individual s with hearing loss or Usher syndrome, but has been identified in 28/121364 chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs144783615). Although this variant has been seen in the general popula tion, its frequency is not high enough to rule out a pathogenic role. Computatio nal prediction tools and conservation analysis suggest that this variant may imp act the protein, though this information is not predictive enough to determine p athogenicity. In summary, the clinical significance of the p.Arg4081Trp variant is uncertain.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000756891 SCV000884859 uncertain significance not provided 2017-12-29 criteria provided, single submitter clinical testing The USH2A p.Arg4081Trp variant (rs144783615) has not been reported in the medical literature. However, the p.Arg4081Trp is listed in the Genome Aggregation Database (gnomAD) browser with an allele frequency of 0.14% in the African population (identified in 34 out of 24,020 chromosomes), and it is classified as a variant of uncertain significance in ClinVar (Variant ID: 229617). The arginine at codon 4081 is moderately conserved considering 12 species (Alamut software v2.10.0), and computational analyses predict that this variant does affect the structure/function of the USH2A protein (SIFT: damaging, PolyPhen2: possibly damaging, MutationTaster: disease causing). However, based on the available information, the clinical significance of the p.Arg4081Trp variant cannot be determined with certainty.
Invitae RCV000756891 SCV001197614 likely benign not provided 2024-01-29 criteria provided, single submitter clinical testing
GeneDx RCV000756891 SCV001987416 uncertain significance not provided 2022-12-10 criteria provided, single submitter clinical testing Identified in a patient with retinitis pigmentosa in published literature, however the individual's second reported USH2A variant is currently classified as benign (Qu et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31904091)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000217686 SCV002571068 uncertain significance not specified 2022-07-29 criteria provided, single submitter clinical testing Variant summary: USH2A c.12241C>T (p.Arg4081Trp) results in a non-conservative amino acid change located in the Fibronectin type III domain of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00025 in 251166 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in USH2A causing Usher Syndrome (0.00025 vs 0.011), allowing no conclusion about variant significance. c.12241C>T has been reported in the literature in at least one individual affected with non-syndromic retinitis pigmentosa. This report does not provide unequivocal conclusions about association of the variant with Usher Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc. RCV001274936 SCV001459518 uncertain significance Usher syndrome type 2A 2020-01-17 no assertion criteria provided clinical testing

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