ClinVar Miner

Submissions for variant NM_206933.4(USH2A):c.7595-3C>G

gnomAD frequency: 0.00003  dbSNP: rs201657446
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000178475 SCV000230558 likely pathogenic not provided 2014-06-26 criteria provided, single submitter clinical testing
Counsyl RCV000669197 SCV000793926 pathogenic Usher syndrome type 2A; Retinitis pigmentosa 39 2017-09-12 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000178475 SCV001202174 pathogenic not provided 2024-01-19 criteria provided, single submitter clinical testing This sequence change falls in intron 40 of the USH2A gene. It does not directly change the encoded amino acid sequence of the USH2A protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs201657446, gnomAD 0.002%). This variant has been observed in individual(s) with Usher syndrome type II (PMID: 17405132, 22135276, 24944099, 25097241, 26969326). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 197447). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 20052763). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV001075871 SCV001241512 pathogenic Retinal dystrophy 2019-08-14 criteria provided, single submitter clinical testing
GeneDx RCV000178475 SCV001811549 pathogenic not provided 2024-02-09 criteria provided, single submitter clinical testing Results in gain of a new acceptor splice site in intron 40; Published minigene assays demonstrate abnormal gene splicing with insertion of intronic sequence in the open reading frame, resulting in a frameshift and premature termination of translation (PMID: 20052763); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 25649381, 24944099, 27208204, 34758253, 25097241, 22135276, 27460420, 20052763, 17405132, 26969326, 28981474, 28041643, 32176120, 32581362, 31589614, 36011334, 34948090, 31816670, 35266249, 31964843, 36819107)
Fulgent Genetics, Fulgent Genetics RCV000669197 SCV002793763 pathogenic Usher syndrome type 2A; Retinitis pigmentosa 39 2022-01-08 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV003445607 SCV004172074 likely pathogenic Retinitis pigmentosa 39 2023-04-11 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV001542728 SCV004172075 likely pathogenic Usher syndrome type 2A 2023-04-11 criteria provided, single submitter clinical testing
Baylor Genetics RCV003445607 SCV004208162 likely pathogenic Retinitis pigmentosa 39 2023-12-20 criteria provided, single submitter clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge RCV000504696 SCV000598829 likely pathogenic Usher syndrome 2015-01-01 no assertion criteria provided research
Genomics England Pilot Project, Genomics England RCV001542728 SCV001760013 pathogenic Usher syndrome type 2A no assertion criteria provided clinical testing
Natera, Inc. RCV001542728 SCV002090852 pathogenic Usher syndrome type 2A 2020-09-30 no assertion criteria provided clinical testing
PreventionGenetics, part of Exact Sciences RCV004537466 SCV004116761 pathogenic USH2A-related disorder 2024-08-20 no assertion criteria provided clinical testing The USH2A c.7595-3C>G variant is predicted to interfere with splicing. This variant has been reported to be causative for autosomal recessive Usher syndrome type 2 (Baux et al. 2007. PubMed ID: 17405132; Sloan-Heggen et al. 2016. PubMed ID: 26969326; Le Guédard-Méreuze et al. 2010. PubMed ID: 20052763). Ex vivo splicing assays showed that this variant leads to aberrant splicing (Le Guédard-Méreuze et al. 2010. PubMed ID: 20052763). This variant is reported in 0.0027% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.

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