ClinVar Miner

Submissions for variant NM_052995.2(CLRN1):c.205+1061A>T (rs567709615)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000219342 SCV000271588 uncertain significance not specified 2018-11-07 criteria provided, single submitter clinical testing The c.434-2A>T variant in CLRN1 has been previously identified by our laboratory in five individuals with hearing loss, but none of these individuals had a vari ant affecting the remaining copy of the CLRN1 gene. This variant has been identi fied in 0.12% (81/68182) of European chromosomes by the Genome Aggregation Datab ase (http://gnomad.broadinstitute.org/). This variant is located at the -2 splic e site position near exon 3 of an alternate transcript (NM_001195794.1) of the C LRN1 gene, and is predicted to impact splicing of this transcript. However, in a ll other transcripts of the gene, including the major transcript (NM_174878.2), the variant lies in an intronic region that is distant from the splice sites of exons expressed in those transcripts and is not predicted to impact their splici ng. While this alternate transcript (NM_001195794.1) is reportedly expressed in the retina (Vastinsalo 2011), to date, pathogenic variants have not been reporte d in exon 3 of this transcript in individuals with Usher syndrome. Therefore, it is not clear whether abnormal splicing affecting only the alternate transcript can cause disease. In summary, the clinical significance of this variant is unce rtain. ACMG/AMP Criteria applied: PP3, BS1_Supporting.
GeneDx RCV000766844 SCV000571506 uncertain significance not provided 2016-09-12 criteria provided, single submitter clinical testing The c.434-2A>T variant in the CLRN1 gene has been reported previously in an individual with Usher syndrome, however a second variant was not identified (Bonnet et al., 2016). This splice site variant destroys the canonical splice acceptor site in intron 2. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.434-2A>T variant was not observed with any significant frequency in the Exome Aggregation Consortium (ExAC) data set, indicating it is not a common benign variant. We interpret c.434-2A>T as a variant of uncertain significance.
Counsyl RCV000664764 SCV000788774 uncertain significance Usher syndrome, type 3A 2016-12-15 criteria provided, single submitter clinical testing

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