ClinVar Miner

Submissions for variant NM_206933.4(USH2A):c.4576G>A (p.Gly1526Arg)

gnomAD frequency: 0.00001  dbSNP: rs769198746
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV001075822 SCV001241458 pathogenic Retinal dystrophy 2019-07-19 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001381658 SCV001580147 pathogenic not provided 2024-08-13 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1526 of the USH2A protein (p.Gly1526Arg). This variant is present in population databases (rs769198746, gnomAD 0.02%). This missense change has been observed in individual(s) with Usher syndrome and retinitis pigmentosa (PMID: 25356976, 26310143, 30948794). 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: 867207). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt USH2A protein function with a positive predictive value of 95%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
3billion, Medical Genetics RCV002250723 SCV002520989 pathogenic Usher syndrome type 2A 2022-05-22 criteria provided, single submitter clinical testing Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000867207). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 25356976, 26310143). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.62; 3Cnet: 3CNET). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Genome-Nilou Lab RCV003455425 SCV004182221 pathogenic Retinitis pigmentosa 39 2023-11-04 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV002250723 SCV004182222 pathogenic Usher syndrome type 2A 2023-11-04 criteria provided, single submitter clinical testing
Baylor Genetics RCV003455425 SCV004208256 pathogenic Retinitis pigmentosa 39 2023-12-27 criteria provided, single submitter clinical testing

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