ClinVar Miner

Submissions for variant NM_206933.4(USH2A):c.11927C>T (p.Thr3976Met) (rs142381713)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000041707 SCV000065403 likely benign not specified 2016-05-05 criteria provided, single submitter clinical testing p.Thr3976Met in exon 61 of USH2A: This variant is not expected to have clinical significance because it occurs in cis with a pathogenic variant in one individua l with Usher syndrome (Baux 2007, Le Guedard-Mereuze 2010). It has been identifi ed in 0.1% (56/66702) of European chromosomes by the Exome Aggregation Consortiu m (ExAC, http://exac.broadinstitute.org; dbSNP rs142381713).
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000725418 SCV000336817 uncertain significance not provided 2015-10-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000041707 SCV000605543 uncertain significance not specified 2019-05-10 criteria provided, single submitter clinical testing The p.Thr3976Met variant (rs142381713) has been observed as part of a complex allele with a different variant, c.3811+3A>T, found in an individual with a clinical diagnosis of Usher syndrome type II (Baux 2007). In addition to this complex allele, the patient in Baux (2007) also carried a clearly pathogenic nonsense variant (p.Leu2301Ter) in trans. Subsequent in vitro analysis of the c.3811+3A>T variant indicated that it almost completely disrupts splicing, leading to skipping of exon 17 (Le Guedard-Mereuze 2010). The c.3811+3A>T variant is also absent from population databases such as 1000 Genomes, the NHLBI GO Exome Sequencing Project (ESP), and the Exome Aggregation Consortium (ExAC) browser. As a comparison, p.Thr3976Met is listed in the ESP with an allele frequency in European Americans of 0.14% (identified in 12 out of 8,600 chromosomes), and in the ExAC browser with an allele frequency in non-Finnish Europeans of 0.08% (identified in 56 out of 66,702 chromosomes). These observations argue that the c.3811+3A>T is pathogenic, and thus it is likely that the p.Thr3976Met variant is not. However, skipping of exon 17 retains the reading frame of USH2A mRNA, and the c.3811+3A>T variant has not been reported with any other pathogenic alleles. Moreover, the threonine at codon 3976 is highly conserved considering 10 species up to chicken (Alamut software v2.7.1), and computational analyses suggest the p.Thr3976Met variant has a significant effect on USH2A protein structure/function (SIFT: damaging, PolyPhen2: probably damaging, and Mutation Taster: disease causing). Therefore, with the uncertainty concerning the pathogenicity of the c.3811+3A>T variant, and the lack of other evidence suggesting the p.Thr3976Met variant is benign, the clinical significance of the p.Thr3976Met variant cannot be determined with certainty.
Mendelics RCV000986519 SCV001135534 benign Usher syndrome, type 2A 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000725418 SCV001147666 uncertain significance not provided 2019-01-01 criteria provided, single submitter clinical testing
Invitae RCV000725418 SCV001207326 uncertain significance not provided 2020-01-03 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 3976 of the USH2A protein (p.Thr3976Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs142381713, ExAC 0.08%). This variant has been reported in individuals affected with Usher syndrome and retinitis pigmentosa (PMID: 17405132, 25910913, 28181551). ClinVar contains an entry for this variant (Variation ID: 48385). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000041707 SCV000730477 likely benign not specified 2018-02-26 no assertion criteria provided clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

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