ClinVar Miner

Submissions for variant NM_206933.4(USH2A):c.12295-3T>A (rs111033518)

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Total submissions: 9
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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 likely pathogenic Usher syndrome 2019-10-23 reviewed by expert panel curation The c.12295-3T>A variant is present in 5/127918 (0.0039%) of European (non-Finnish) chromosomes in gnomAD (PM2). The variant has also been identified in 2 probands with hearing loss, one of whom was diagnosed with Usher syndrome and both probands also harbored the pathogenic p.Glu767Serfs*21 variant in USH2A (PM3, PP4). 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 likely pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied as specified by the ClinGen Hearing Loss Expert Panel (PVS1_Strong, PM3, PM2, PP4).
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV001004773 SCV000065413 pathogenic Usher syndrome 2019-02-07 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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)
Invitae RCV000414389 SCV001207341 pathogenic not provided 2020-07-03 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, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs111033518, ExAC 0.002%). This variant has been observed in individual(s) with clinical features of USH2A-related disease (PMID: 25649381, 25910913, 22135276). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 48395). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 25649381). 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 Institute Rare Disease Group, Broad Institute 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.
Counsyl RCV000675157 SCV000800773 likely pathogenic Retinitis pigmentosa 39 2017-06-21 no assertion criteria provided clinical testing

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