ClinVar Miner

Submissions for variant NM_206933.4(USH2A):c.12295-3T>A

gnomAD frequency: 0.00006  dbSNP: rs111033518
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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 RCV001004773 SCV001164255 pathogenic Usher syndrome 2022-10-31 reviewed by expert panel curation The c.12295-3T>A variant in USH2A is an intronic variant located within the acceptor splice consensus sequence of intron 62. The highest population minor allele frequency in gnomAD v2.1.1 is 0.000039 (5/127918 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.00007) for PM2_Supporting, meeting this criterion (PM2_Supporting). The variant has been identified in 4 individuals with clinical features or diagnosis of Usher syndrome with hearing loss (PMID: 25649381, 22135276; PP4). Three of these individuals were compound heterozygous, phase unknown, with the pathogenic p.Glu767Serfs*21 USH2A variant. The fourth individual harbored the Tyr4031* variant in USH2A, which was likely in trans as shown through RT-PCR sequencing (PM3_Strong). While this variant does not occur within the canonical splice site (±1,2), it has been shown to cause out-of-frame exon skipping in patient-derived cells and pathogenic variants in this exon have been reported in ClinVar (PVS1_Strong, PMID:25649381). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied as specified by the ClinGen Hearing Loss VCEP: PVS1_Strong, PM3_Strong, PM2_Supporting, PP4 (ClinGen Hearing Loss VCEP specifications version 2; 10/31/2022).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV001004773 SCV000065413 pathogenic Usher syndrome 2019-02-07 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Eurofins Ntd Llc (ga) RCV000414389 SCV000231910 pathogenic not provided 2015-04-27 criteria provided, single submitter clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia RCV000041717 SCV000297410 uncertain significance not specified 2015-08-10 criteria provided, single submitter clinical testing
GeneDx RCV000414389 SCV000490875 pathogenic not provided 2021-09-13 criteria provided, single submitter clinical testing RNA functional studies of the c.12295-3T>A variant demonstrate out-of-frame skipping of exon 63 which leads to the expression of a smaller transcript and results in a premature termination codon (Lenassi et al., 2015); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 22135276, 25910913, 25649381)
Labcorp Genetics (formerly Invitae), Labcorp RCV000414389 SCV001207341 pathogenic not provided 2024-01-11 criteria provided, single submitter clinical testing This sequence change falls in intron 62 of the USH2A gene. It does not directly change the encoded amino acid sequence of the USH2A protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs111033518, gnomAD 0.005%). This variant has been observed in individual(s) with clinical features of USH2A-related disease (PMID: 22135276, 25649381, 25910913). 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: 48395). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in exon 63 skipping and introduces a premature termination codon (PMID: 25649381). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV001074786 SCV001240382 pathogenic Retinal dystrophy 2019-06-24 criteria provided, single submitter clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV001723628 SCV001950394 likely pathogenic Retinitis pigmentosa 2021-04-01 criteria provided, single submitter curation The c.12295-3T>A 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: PS3, PM2. Based on this evidence we have classified this variant as Likely Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.
Baylor Genetics RCV000675157 SCV004208354 pathogenic Retinitis pigmentosa 39 2024-03-21 criteria provided, single submitter clinical testing
Counsyl RCV000675157 SCV000800773 likely pathogenic Retinitis pigmentosa 39 2017-06-21 no assertion criteria provided clinical testing

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