Submissions for variant NM_206933.4(USH2A):c.8342C>T (p.Thr2781Ile)

gnomAD frequency: 0.00011  dbSNP: rs143240767

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041924	SCV000065620	likely benign	not specified	2014-10-17	criteria provided, single submitter	clinical testing	Thr2781Ile in exon 42 of USH2A: This variant is not expected to have clinical si gnificance because it has been identified in 2.8% (5/178) of Japanese chromosome s by the 1000 Genomes project (rs143240767). While it has been identified in on e individual with hearing loss (Yang 2013), based on the population frequency, t his variant is likely benign.
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000490269	SCV000267555	uncertain significance	Usher syndrome type 2A	2016-03-18	criteria provided, single submitter	reference population
Counsyl	RCV000665134	SCV000789200	uncertain significance	Usher syndrome type 2A; Retinitis pigmentosa 39	2017-01-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000937215	SCV001082991	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing
Mendelics	RCV000490269	SCV001135543	benign	Usher syndrome type 2A	2019-05-28	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000490269	SCV001716391	likely benign	Usher syndrome type 2A	2021-05-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001579280	SCV001806751	likely benign	Retinitis pigmentosa 39	2021-07-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000041924	SCV002051325	likely benign	not specified	2021-12-22	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.8342C>T (p.Thr2781Ile) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.001 in 301738 control chromosomes, predominantly at a frequency of 0.012 within Japanese subpopulation (gnomAD, other databases, publication data). This frequency is equal to the estimated maximal expected allele frequency of a pathogenic variant in USH2A causing Usher Syndrome (0.012 vs 0.011), suggesting this may be a benign polymorphism found primarily in Japanese subpopulation. c.8342C>T has been reported in the literature in deaf patients (Yang_2013, He_2018). These reports do not provide unequivocal conclusions about association of the variant with Usher Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=2), likely benign (n=4) and benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Dept Of Ophthalmology, Nagoya University	RCV003888409	SCV004707925	benign	Retinal dystrophy	2023-10-01	criteria provided, single submitter	research
GeneDx	RCV000937215	SCV005078181	uncertain significance	not provided	2024-07-05	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in patients with USH2A-related disorders together with variants of uncertain significance (phase unknown) in the USH2A gene in published literature (PMID: 36819107, 23767834); This variant is associated with the following publications: (PMID: 36819107, 30245029, 23767834)
Natera, Inc.	RCV000490269	SCV001458112	likely benign	Usher syndrome type 2A	2020-09-16	no assertion criteria provided	clinical testing