ClinVar Miner

Submissions for variant NM_206933.4(USH2A):c.9921T>G (p.Cys3307Trp)

gnomAD frequency: 0.00002  dbSNP: rs1057519382
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel RCV001004786 SCV001164271 uncertain significance Usher syndrome 2024-02-21 reviewed by expert panel curation The variant NM_206933.4:c.9921T>G in USH2A is a missense variant predicted to cause substitution of cysteine by tryptophan at amino acid 3307 (p.Cys3307Trp). The variant is absent from gnomAD v2.1.1 (PM2_Supporting). The REVEL computational prediction analysis tool produced a score of 0.585, which meets no codes. The variant has been reported in three compound heterozygous probands, two who were diagnosed with retinitis pigmentosa, and all with a likely pathogenic/pathogenic second USH2A variant in phase unknown (PM3; PMIDs: 32531858, 34906470, 36819107). In summary, this variant meets the criteria to be classified as uncertain significance for AR Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM2_Supporting, PM3. (ClinGen Hearing Loss VCEP specifications version 2; 2/21/2024).
Counsyl RCV000675100 SCV000800635 uncertain significance Usher syndrome type 2A; Retinitis pigmentosa 39 2017-12-12 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001056911 SCV001221376 pathogenic not provided 2024-01-16 criteria provided, single submitter clinical testing This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 3307 of the USH2A protein (p.Cys3307Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 26667666, 32531858; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 226441). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on USH2A protein function. This variant disrupts the p.Cys3307Tyr amino acid residue in USH2A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28559085; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen RCV001056911 SCV001246989 pathogenic not provided 2018-04-01 criteria provided, single submitter clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear RCV001376499 SCV001573670 uncertain significance Retinitis pigmentosa 39 2021-04-08 criteria provided, single submitter research The USH2A c.9921T>G variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2. Based on this evidence we have classified this variant as Variant of Uncertain Significance.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV001723791 SCV001950418 uncertain significance Retinitis pigmentosa 2021-04-01 criteria provided, single submitter curation The p.Cys3307Trp variant in USH2A was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PM2. Based on this evidence we have classified this variant as a Variant of Uncertain Significance. If you have any questions about the classification please reach out to the Pierce Lab.
Fulgent Genetics, Fulgent Genetics RCV000675100 SCV002789327 uncertain significance Usher syndrome type 2A; Retinitis pigmentosa 39 2021-12-01 criteria provided, single submitter clinical testing
GeneReviews RCV000216234 SCV000268766 likely pathogenic Usher syndrome type 1 2016-05-19 no assertion criteria provided literature only
Natera, Inc. RCV001833176 SCV002088378 uncertain significance Usher syndrome type 2A 2020-12-10 no assertion criteria provided clinical testing
PreventionGenetics, part of Exact Sciences RCV004732790 SCV005357665 likely pathogenic USH2A-related disorder 2024-08-22 no assertion criteria provided clinical testing The USH2A c.9921T>G variant is predicted to result in the amino acid substitution p.Cys3307Trp. This variant has been reported along with a second USH2A variant in multiple individuals with Usher syndrome or retinal disease (Bonnet et al. 2011. PubMed ID: 21569298; Ge et al. 2015. PubMed ID: 26667666; Table S1, Weisschuh et al. 2020. PubMed ID: 32531858; Table S4, Panneman et al. 2023. PubMed ID: 36819107). An alternate substitution of this amino acid residue (p.Cys3307Tyr) has also been reported in individuals with Usher syndrome or retinal disease (Table S1, Stone et al. 2017. PubMed ID: 28559085). This variant has not been reported in a large population database, indicating this variant is rare. Given the evidence, we interpret this variant as likely pathogenic.

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