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

gnomAD frequency: 0.00049  dbSNP: rs142381713

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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).
Eurofins Ntd Llc (ga)	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.
GeneDx	RCV000725418	SCV000730477	likely benign	not provided	2020-10-29	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 28181551, 17405132, 25910913, 20052763, 30245029, 32579692, 33576794)
Mendelics	RCV000986519	SCV001135534	benign	Usher syndrome type 2A	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000725418	SCV001147666	uncertain significance	not provided	2023-01-01	criteria provided, single submitter	clinical testing	USH2A: PM2, BP4
Invitae	RCV000725418	SCV001207326	uncertain significance	not provided	2022-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 3976 of the USH2A protein (p.Thr3976Met). This variant is present in population databases (rs142381713, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with retinitis pigmentosa and/or Usher syndrome (PMID: 17405132, 25910913, 28181551, 33576794). 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. 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.
Genome-Nilou Lab	RCV000986519	SCV001653362	uncertain significance	Usher syndrome type 2A	2021-05-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001579153	SCV001806577	uncertain significance	Retinitis pigmentosa 39	2021-07-22	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV000725418	SCV001923763	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000725418	SCV001963917	uncertain significance	not provided		no assertion criteria provided	clinical testing