ClinVar Miner

Submissions for variant NM_206933.4(USH2A):c.5857+2T>C (rs397518022)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel RCV001004785 SCV001164270 likely pathogenic Usher syndrome 2019-10-29 reviewed by expert panel curation The c.5857+2T>C variant in USH2A has been identified in at least 3 probands with Usher syndrome, including two who were compound heterozygous for a second pathogenic variant though phase was not confirmed (PM3, PP4; PMID 20507924, 20507924, 18641288, LMM unpublished data SCV000065566.6). The allele frequency of this variant is 0.01% (2/15422) of European chromosomes by gnomAD, which is a low enough frequency to apply PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_Supporting). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing, though the exact impact is unknown. Exon 29 is in-frame, and if the variant results in exon skipping, it would remove <10% of the USH2A protein. However, two truncating pathogenic / likely pathogenic variants in this exon have been reported in ClinVar, which may suggest it is required for normal protein function (PVS1_Moderate). 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 Hearing Loss Expert Panel (PVS1_Moderate, PM3, PP4, PM2_Supporting).
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000041870 SCV000065566 pathogenic Rare genetic deafness 2013-03-11 criteria provided, single submitter clinical testing The 5857+2T>C variant has been reported in 2 probands with the clinical features of Usher syndrome type II, one of whom carried a second pathogenic USH2A varian t (Sandberg 2008, McGee 2010). This variant occurs in the invariant region (+1/2 ) of the 5' splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. In summary, this variant meets our cr iteria to be classified as pathogenic (http://pcpgm.partners.org/LMM).
Illumina Clinical Services Laboratory,Illumina RCV000295857 SCV000354057 uncertain significance USH2A-Related Disorders 2016-06-14 criteria provided, single submitter clinical testing The c.5857+2T>C variant variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The variant has been described in two studies in which it was found in a compound heterozygous state in one individual with autosomal recessive retinitis pigmentosa, and in a heterozygous state in two individuals with Usher syndrome type II (Sandberg et al. 2008; McGee et al. 2010). Control data are unavailable for this variant which is also not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. Due to the potential impact of splice donor variants and the supporting evidence from the literature, this variant is classified as a variant of unknown significance, but suspicious for pathogenicity for USH2A-related disorders.
Invitae RCV001036145 SCV001199495 likely pathogenic not provided 2019-12-23 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 29 of the USH2A gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). Disruption of this splice site has been observed in individuals affected with USH2A-related conditions (PMID: 18641288, 20507924). ClinVar contains an entry for this variant (Variation ID: 48544). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in USH2A are known to be pathogenic (PMID: 10729113, 10909849, 20507924, 25649381). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Blueprint Genetics RCV001074605 SCV001240196 pathogenic Retinal dystrophy 2019-01-16 criteria provided, single submitter clinical testing
Counsyl RCV000675153 SCV000800763 likely pathogenic Retinitis pigmentosa 39 2017-05-09 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.