ClinVar Miner

Submissions for variant NM_206933.4(USH2A):c.9371+1G>C (rs41308425)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000041950 SCV000065646 pathogenic Rare genetic deafness 2016-06-23 criteria provided, single submitter clinical testing The c.9371+1G>C variant in USH2A has been reported in 5 individuals with Usher s yndrome with 4 of these individuals being compound heterozygous with a second pa thogenic USH2A variant (Le Quesne Stabej 2012, Zein 2015, Lenassi 2015, LMM data ). This 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 a bsent protein. Loss of function of the USH2A gene is an established disease mech anism in autosomal recessive Usher syndrome. In summary, this variant meets our criteria to be classified as pathogenic for autosomal recessive Usher syndrome b ased on the predicted impact of the variant.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000726813 SCV000703232 pathogenic not provided 2016-11-30 criteria provided, single submitter clinical testing
Centre for Genomic Medicine, Manchester,Central Manchester University Hospitals RCV001002711 SCV001156383 pathogenic Usher syndrome, type 2A 2019-02-01 criteria provided, single submitter clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear RCV001376451 SCV001573592 pathogenic Retinitis pigmentosa 39 2021-04-08 criteria provided, single submitter research The USH2A c.9371+1G>C variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PVS1, PM2, PP3. Based on this evidence we have classified this variant as Pathogenic.
Invitae RCV000726813 SCV001579752 pathogenic not provided 2020-07-29 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 47 of the USH2A gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs41308425, ExAC 0.001%). Disruption of this splice site has been observed in individual(s) with retinitis pigmentosa or Usher syndrome (PMID: 22135276, 26377068, 24938718). ClinVar contains an entry for this variant (Variation ID: 48624). 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.
GeneDx RCV000726813 SCV001804845 pathogenic not provided 2020-04-20 criteria provided, single submitter clinical testing Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 32176120, 25425308, 25649381, 26377068, 22135276, 24938718)

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