ClinVar Miner

Submissions for variant NM_206933.4(USH2A):c.651+1G>A

dbSNP: rs1553257761
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000668857 SCV000793530 likely pathogenic Usher syndrome type 2A; Retinitis pigmentosa 39 2017-08-24 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001054302 SCV001218610 pathogenic not provided 2023-11-27 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 3 of the USH2A gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with Usher syndrome (PMID: 22135276, 34948090). ClinVar contains an entry for this variant (Variation ID: 553412). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001526995 SCV001737798 likely pathogenic Usher syndrome 2023-07-19 criteria provided, single submitter clinical testing Variant summary: USH2A c.651+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250564 control chromosomes. c.651+1G>A has been reported in the literature in compound heterozygous individuals affected with Usher Syndrome (e.g. Stabej_2012, Mansard_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34948090, 22135276). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Genome-Nilou Lab RCV003446302 SCV004172220 likely pathogenic Retinitis pigmentosa 39 2023-04-11 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV003446301 SCV004172221 likely pathogenic Usher syndrome type 2A 2023-04-11 criteria provided, single submitter clinical testing

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