Submissions for variant NM_206933.4(USH2A):c.7068T>G (p.Asn2356Lys)

gnomAD frequency: 0.00051  dbSNP: rs200038092

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041902	SCV000065598	benign	not specified	2017-09-04	criteria provided, single submitter	clinical testing
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000490376	SCV000267556	uncertain significance	Usher syndrome type 2A	2016-03-18	criteria provided, single submitter	reference population
Counsyl	RCV000671627	SCV000796617	uncertain significance	Usher syndrome type 2A; Retinitis pigmentosa 39	2017-12-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000924303	SCV001069814	benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Mendelics	RCV000490376	SCV001135546	uncertain significance	Usher syndrome type 2A	2019-05-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000924303	SCV001981926	uncertain significance	not provided	2023-03-31	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30073356, 30245029, 23591405, 25356976, 24938718, 25078356, 24853665, 23967202, 26346818, 29625443, 30804660, 32090030, 33105608, 34426522, 33691693, 33090715, 33124170, 35114279, 35860547, 32188678, 32675063, 35836572, 30826590)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000041902	SCV002500134	uncertain significance	not specified	2022-03-05	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.7068T>G (p.Asn2356Lys) 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 damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.001 in 291028 control chromosomes, predominantly at a frequency of 0.01 within the East Asian subpopulation in the gnomAD database and has also been reported as a common variant in the Japanese normal hearing population (example, Moteki_2016). This frequency is close to or almost similar (i.e., not significantly lower) than estimated for a pathogenic variant in USH2A causing Usher Syndrome (0.01 in East Asian cohorts vs 0.011), supporting a benign outcome. In a cross sectional ascertainment spanning 2013-2021, c.7068T>G has been reported in the literature as a VUS and/or non-informative genotype in settings of multigene panel testing predominantly among East Asian cohorts of individuals with a variety of Usher syndrome related manifestations such as hearing loss (example, Miyagawa_2013), sporadic retinal dystrophy (example, Glockle_2014), Inherited Retinal Degeneration cohort (example, Huang_2015), Japanese Normal Hearing cohort (Moteki_2016), Usher syndrome cohort (example, Galli-Resta_2018, Meng_2021), an individual with Usher syndrome compound heterozygous for causative variants in the MYO7A gene (example, Li_2019), possible digenic association proposed in an individual with Inherited Retinal Degeneration (example, Liu_2020). These report(s) 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 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign, n=3; VUS, n=4). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000924303	SCV003800109	benign	not provided	2022-02-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000924303	SCV004125612	benign	not provided	2023-02-01	criteria provided, single submitter	clinical testing	USH2A: BP4, BS1, BS2
Natera, Inc.	RCV000490376	SCV001466773	likely benign	Usher syndrome type 2A	2020-04-03	no assertion criteria provided	clinical testing