Submissions for variant NM_206933.4(USH2A):c.12557T>C (p.Ile4186Thr)

gnomAD frequency: 0.00159  dbSNP: rs112120466

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041722	SCV000065418	likely benign	not specified	2012-05-07	criteria provided, single submitter	clinical testing	Ile4186Thr in Exon 63 of USH2A: This variant is not expected to have clinical si gnificance because it has been identified in 0.6% (22/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs112120466).
GeneDx	RCV000767175	SCV000572702	likely benign	not provided	2020-12-11	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000767175	SCV001062344	benign	not provided	2024-01-26	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV001075259	SCV001240874	uncertain significance	Retinal dystrophy	2017-08-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000041722	SCV005184536	uncertain significance	not specified	2024-05-28	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.12557T>C (p.Ile4186Thr) 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 0.00031 in 1614108 control chromosomes, predominantly at a frequency of 0.0058 within the African or African-American subpopulation in the gnomAD database, including 2 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (0.00031 vs 0.011), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.12557T>C in individuals affected with Usher Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 48400). Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV001274932	SCV001459514	likely benign	Usher syndrome type 2A	2019-11-22	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004537148	SCV004728605	likely benign	USH2A-related disorder	2023-09-05	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).