ClinVar Miner

Submissions for variant NM_206933.2(USH2A):c.3902G>T (p.Gly1301Val) (rs111033524)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000488230 SCV000884865 uncertain significance not provided 2018-06-22 criteria provided, single submitter clinical testing The USH2A c.3902G>T; p.Gly1301Val variant (rs111033524) is reported in the medical literature in individuals with Usher syndrome and retinitis pigmentosa, however, one of these individuals also carried an alternate molecular explanation for disease (Bonnet 2011, Pierrache 2016). The variant is reported with discrepant classifications in the ClinVar database (Variation ID: 48509) and in the Genome Aggregation Database in 0.6% (184/30778 alleles) of the South Asian population. The glycine at this codon is moderately conserved but computational analyses (SIFT:Tolerated, PolyPhen-2: Probably Damaging) predict conflicting effects of this variant on protein structure/function. Although there is information indicating this variant may not be pathogenic, there is insufficient evidence to classify the variant with certainty. Pathogenic USH2A variants are causative for autosomal recessive Usher syndrome (MIM: 276901) and retintitis pigmentosa (MIM: 613809). References: Bonnet C et al. Complete exon sequencing of all known Usher syndrome genes greatly improves molecular diagnosis. Orphanet J Rare Dis. 2011 May 11;6:21. Pierrache LH et al. Visual Prognosis in USH2A-Associated Retinitis Pigmentosa Is Worse for Patients with Usher Syndrome Type IIa Than for Those with Nonsyndromic Retinitis Pigmentosa. Ophthalmology. 2016 May;123(5):1151-60.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000488230 SCV000574821 uncertain significance not provided 2016-10-31 criteria provided, single submitter clinical testing
ClinGen Hearing Loss Variant Curation Expert Panel, RCV000787994 SCV000927022 benign Usher syndrome type 2 2019-02-25 reviewed by expert panel curation The filtering allele frequency of the p.Gly1301Val variant in the USH2A gene is 0.52% for South Asian chromosomes by gnomAD (183/30608 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive Usher syndrome variants (BA1).
GeneReviews RCV000219904 SCV000268767 likely pathogenic Usher syndrome, type 1 2016-05-19 no assertion criteria provided literature only
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000041835 SCV000065531 likely benign not specified 2010-04-22 criteria provided, single submitter clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge RCV000505069 SCV000598808 likely pathogenic Retinitis pigmentosa 2015-01-01 no assertion criteria provided research

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