ClinVar Miner

Submissions for variant NM_206933.4(USH2A):c.12067-2A>G (rs397517978)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000390593 SCV000065408 pathogenic Rare genetic deafness 2013-05-13 criteria provided, single submitter clinical testing The 12067-2A>G variant in USH2A has been reported in five individuals with Usher syndrome type 2, one individual with autosomal recessive retinitis pigmentosa a nd one individual with congenital sensorineural hearing loss (Sandberg 2008, Aus lender 2008, Garcia-Garcia 2011, LMM unpublished data). Four of these probands w ere homozygous or compound heterozygous. Segregation of this variant with disea se was demonstrated in two affected family members (Auslender 2008). In addition , 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 ab sent protein. In summary, this variant meets our criteria to be classified as pa thogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000412841 SCV000341017 pathogenic not provided 2016-05-10 criteria provided, single submitter clinical testing
GeneDx RCV000412841 SCV000490873 pathogenic not provided 2018-03-08 criteria provided, single submitter clinical testing The c.12067-2 A>G splice site variant has been previously reported in association with Usher syndrome (Auslender et al., 2008; Aparisi et al., 2014; Tekin et al., 2016). This variant destroys the canonical splice acceptor site in intron 61, and is expected to cause abnormal gene splicing. The variant is observed in 15/33530 (0.045%) alleles from individuals of Latino background in large population cohorts (Lek et al., 2016). In summary, we consider c.12067-2 A>G to be pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000666727 SCV000893284 pathogenic Usher syndrome, type 2A; Retinitis pigmentosa 39 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000412841 SCV000933043 pathogenic not provided 2019-12-06 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 61 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 (rs397517978, ExAC 0.07%). This variant has been observed to segregate with Usher syndrome in a family and has been reported in individuals affected with Usher syndrome (PMID: 18452394, 25404053, 22004887) or pericentral retinitis pigmentosa (PMID: 28981474). ClinVar contains an entry for this variant (Variation ID: 48390). 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.
Blueprint Genetics RCV001073917 SCV001239482 pathogenic Retinal dystrophy 2018-06-19 criteria provided, single submitter clinical testing
Counsyl RCV000983997 SCV000791074 pathogenic Retinitis pigmentosa 39 2017-04-24 no assertion criteria provided clinical testing
Sharon lab,Hadassah-Hebrew University Medical Center RCV001003259 SCV001161341 pathogenic Usher syndrome type 2 2019-06-23 no assertion criteria provided research

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