ClinVar Miner

Submissions for variant NM_206933.3(USH2A):c.8559-2A>G (rs397518039)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel, RCV000710341 SCV000840538 pathogenic Usher syndrome 2018-10-09 reviewed by expert panel curation The c.8559-2A>G has been detected in >4 patients with Usher syndrome who were compound heterozygous for the this variant in trans with a truncating variant (PM3_VS; PMID: 25356976, 19737284, 26338283, 19023448). Segregation data was also available for two reported families with Usher syndrome. In one family, the variant was identified in trans with a frameshift variant in two affected siblings, and four unaffected siblings were either heterozygous for a single variant or wild-type for both variants. In the second family, an unaffected sibling was heterozygous for a single variant (PP1_Strong, PMID: 19023448). RT-PCR analysis of cells from a patient carrying the variant revealed that the variant causes skipping of exon 43, resulting in a 41 amino acid deletion of the USH2A protein (PM4, PMID: 20596040) The allele frequency of the c.8559-2A>G variant in the USH2A gene is 0.046% (8/17232) of East Asian chromosomes by the Genome Aggregation Database ( http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2_supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss and Usher syndrome (PM2_Supporting). Several patients reported to harbor this variant displayed clinical features of Usher syndrome (PP4; PMID: 25356976, 19737284, 26338283, 19023448). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM4, PM3_VS, PP1_S, PP4, PM2_P.
Counsyl RCV000665497 SCV000789631 pathogenic Usher syndrome, type 2A; Retinitis pigmentosa 39 2017-02-08 criteria provided, single submitter clinical testing
Department of Ophthalmology and Visual Sciences Kyoto University RCV000132715 SCV000172669 pathogenic Retinitis pigmentosa no assertion criteria provided not provided Converted during submission to Pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000592589 SCV000700946 pathogenic not provided 2017-01-19 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000665497 SCV000893286 pathogenic Usher syndrome, type 2A; Retinitis pigmentosa 39 2018-10-31 criteria provided, single submitter clinical testing
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery,Institute of Otolaryngology, Chinese PLA General Hospital RCV000041930 SCV000902401 pathogenic Usher syndrome, type 2A 2019-02-26 no assertion criteria provided case-control
Invitae RCV000592589 SCV000938861 pathogenic not provided 2018-10-20 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 42 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 (rs397518039, ExAC 0.03%). This variant has been observed in individuals affected with Usher syndrome, and has been shown to segregate with disease in a family (PMID: 19023448, 19737284). ClinVar contains an entry for this variant (Variation ID: 48604). 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000824785 SCV000065626 pathogenic Rare genetic deafness 2011-09-12 criteria provided, single submitter clinical testing The 8559-2A>G variant in USH2A has been reported in 6 Asian individuals with Ush er type 2 and was absent in 470 Asian control chromosomes (Dai 2008, Nakanishi 2 009). All of these probands were compound heterozygous. This variant is predicte d to cause abnormal splicing because the nucleotide substitution occurs in the i nvariant region of the splice consensus sequence. Furthermore, RT-PCR analysis o f cells from a patient carrying the variant revealed that the variant causes ski pping of exon 43, resulting in a 41 amino acid deletion of the USH2A protein (Na kanishi 2010). In summary, this variant meets our criteria to be classified as p athogenic.

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