ClinVar Miner

Submissions for variant NM_206933.4(USH2A):c.5776+1G>A (rs876657731)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000213465 SCV000271472 pathogenic Rare genetic deafness 2015-04-02 criteria provided, single submitter clinical testing The c.5776+1G>A variant in USH2A has been previously reported in 12 individuals: 9 with Usher syndrome and 2 with retinitis pigmentosa (Baux 2014, Dreyer 2008, Glockle 2014, Jaijo 2010, Lenarduzzi 2015, Lenassi 2015, Sandberg 2008, Sodi 201 4, Wang 2014). Ten of these individuals were either compound heterozygous or hom ozygous for the variant. This variant has not been reported in large population studies. The c.5776+1G>A variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Furthermore, analysis of mRNA extracted from a c arrier of the c.5776+1G>A variant showed in-frame skipping of exon 28 (Lenassi 2 015), confirming a splicing impact. In summary, this variant meets our criteria to be classified as pathogenic for Usher syndrome in an autosomal recessive mann er (www.partners.org/personalizedmedicine/lmm) based upon its identification in the homozygous or compound heterozygous state in multiple affected individuals a nd the reported impact on splicing.
GeneDx RCV000255459 SCV000321998 pathogenic not provided 2018-04-19 criteria provided, single submitter clinical testing The c.5776+1 G>A pathogenic variant in the USH2A gene has been reported previously in the homozygous state or in the heterozygous state along with another USH2A variant in multiple unrelated individuals with Usher syndrome (Sandberg et al., 2008; Jaijo et al., 2010; Wang et al., 2014; Glockle et al., 2014). This variant has also been reported as c.5775+1 G>A due to the use of alternate nomenclature. This splice site variant destroys the canonical splice donor site in intron 28. 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.5776+1 G>A variant is not observed in large population cohorts (Lek et al., 2016). In summary, we consider this variant to be pathogenic.
Centre for Genomic Medicine, Manchester,Central Manchester University Hospitals RCV001002706 SCV001156362 pathogenic Usher syndrome, type 2A 2019-02-01 criteria provided, single submitter clinical testing
Blueprint Genetics RCV001074367 SCV001239943 pathogenic Retinal dystrophy 2019-07-23 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000255459 SCV001247003 pathogenic not provided 2017-10-01 criteria provided, single submitter clinical testing
Department of Otolaryngology – Head & Neck Surgery,Cochlear Implant Center RCV001375185 SCV001571791 pathogenic Usher syndrome 2021-04-12 criteria provided, single submitter clinical testing PVS1_Strong, PS1_Strong, PM2_Moderate, PM3_Supporting
Invitae RCV000255459 SCV001590592 pathogenic not provided 2020-09-27 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 28 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). This variant has been observed in combination with another USH2A variant in individuals affected with Usher syndrome or retinitis pigmentosa (PMID: 25097241, 29490346, 26355662). ClinVar contains an entry for this variant (Variation ID: 228414). 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). For these reasons, this variant has been classified as Pathogenic.
Broad Institute Rare Disease Group, Broad Institute RCV001723796 SCV001950392 pathogenic Retinitis pigmentosa 2021-04-01 criteria provided, single submitter curation The c.5776+1G>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: PVS1, PM2, PM3, PP3. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.
Sharon lab,Hadassah-Hebrew University Medical Center RCV001003271 SCV001161354 pathogenic Usher syndrome type 2 2019-06-23 no assertion criteria provided research
Faculty of Health Sciences,Beirut Arab University RCV001257907 SCV001434723 pathogenic Autosomal recessive retinitis pigmentosa 2015-09-10 no assertion criteria provided literature only
Natera, Inc. RCV001002706 SCV001462252 pathogenic Usher syndrome, type 2A 2020-09-16 no assertion criteria provided clinical testing
Genomics England Pilot Project,Genomics England RCV001542730 SCV001760017 likely pathogenic Retinitis pigmentosa 39 no assertion criteria provided clinical testing

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