ClinVar Miner

Submissions for variant NM_206933.3(USH2A):c.13274C>T (p.Thr4425Met) (rs201238640)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000733677 SCV000861770 uncertain significance not provided 2018-06-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001358731 SCV001554576 pathogenic Usher syndrome 2021-03-26 criteria provided, single submitter clinical testing Variant summary: USH2A c.13274C>T (p.Thr4425Met) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 250930 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in USH2A causing Usher Syndrome (4.4e-05 vs 0.011), allowing no conclusion about variant significance. c.13274C>T has been reported in the literature in multiple individuals affected with Usher Syndrome and autosomal recessive Retinitis Pigmentosa (e.g. van Wijk_2004, Baux_2007, Neverling_2012, van Huet_2015, Bonnet_2016, Toms_2020, Gao_2021). These data indicate that the variant is very likely to be associated with disease. In some of these cases, the variant was reported in complex alleles with p.Arg4115Cys (e.g. van Wijk_2004, Bonnet_2016) and p.Cys759Phe and p.Arg4115Cys (e.g. Baux_2007). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing the variant as likely pathogenic (n=1) and uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
NIHR Bioresource Rare Diseases, University of Cambridge RCV000504678 SCV000598783 likely pathogenic Retinitis pigmentosa 2015-01-01 no assertion criteria provided research

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