Submissions for variant NM_206933.4(USH2A):c.6590C>T (p.Thr2197Ile)

gnomAD frequency: 0.00033  dbSNP: rs140487302

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000152602	SCV000201897	uncertain significance	not specified	2013-09-03	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Thr2197Ile vari ant in USH2A has not been reported in individuals with hearing loss, but has bee n identified in 0.07% (6/8600) of European American chromosomes by the NHLBI Exo me Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs140487302). Al though this variant has been seen in the general population, its frequency is no t high enough to rule out a pathogenic role. Computational analyses (biochemica l amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not pr ovide strong support for or against an impact to the protein. In summary, the cl inical significance of this variant cannot be determined with certainty; however based upon the frequency data described above, we would lean towards a more lik ely benign role.
Counsyl	RCV000669599	SCV000794369	uncertain significance	Usher syndrome type 2A; Retinitis pigmentosa 39	2017-10-06	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001240603	SCV001413568	likely benign	not provided	2025-01-21	criteria provided, single submitter	clinical testing
GeneDx	RCV001240603	SCV001764104	uncertain significance	not provided	2022-12-19	criteria provided, single submitter	clinical testing	Identified in a patient with Usher syndrome who also harbored several other variants in the USH2A gene (phase unknown) in published literature (Carss et al., 2017); 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: 32707200, 30190494, 28041643, 35128159, Hu2022[abstract])
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000152602	SCV002556307	uncertain significance	not specified	2022-06-02	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.6590C>T (p.Thr2197Ile) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 250856 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (0.00029 vs 0.011), allowing no conclusion about variant significance. c.6590C>T has been reported in the literature as a non-informative genotype (second allele not specified, or multiple alleles with/without phase specified) in individuals undergoing analysis for inherited retinal diseases (example, Carss_2017. Gonzalez-del Pozo_2018, Li_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Usher Syndrome. At-least one co-occurrence in cis with another pathogenic variant(s) have been reported (Gonzalez-del Pozo_2018, USH2A c.6590C>T, p.Cys520*), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV000669599	SCV002777825	uncertain significance	Usher syndrome type 2A; Retinitis pigmentosa 39	2022-03-09	criteria provided, single submitter	clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504981	SCV000598822	uncertain significance	Usher syndrome	2015-01-01	no assertion criteria provided	research
Clinical Genetics, Academic Medical Center	RCV001240603	SCV001924912	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001240603	SCV001959396	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001240603	SCV001966331	uncertain significance	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001826815	SCV002090883	uncertain significance	Usher syndrome type 2A	2020-01-24	no assertion criteria provided	clinical testing