Submissions for variant NM_206933.4(USH2A):c.13364C>T (p.Thr4455Ile)

gnomAD frequency: 0.00002  dbSNP: rs373152283

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000756888	SCV000884856	uncertain significance	not provided	2017-06-02	criteria provided, single submitter	clinical testing	The p.Thr4455Ile variant (rs373152283) has not been reported in the medical literature in association with Usher syndrome. This variant is listed in the NHLBI GO Exome Sequencing Project with an overall population frequency of 0.01 percent (identified on 1 out of 13,006 chromosomes) and is listed in the Exome Aggregation Consortium Browser with an overall population frequency of 0.003 percent (identified on 4 out of 121,200 chromosomes). The threonine at position 4455 is moderately conserved (considering 12 species, Alamut v.2.9.0) and computational analyses of the effects of the p.Thr4455Ile variant on protein structure and function provide conflicting results (SIFT: tolerated, MutationTaster: disease causing, PolyPhen-2: possibly damaging). Altogether, there is not enough evidence to classify the p.Thr4455Ile variant with certainty.
CeGaT Center for Human Genetics Tuebingen	RCV000756888	SCV001335222	uncertain significance	not provided	2020-03-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000756888	SCV001995043	uncertain significance	not provided	2019-10-28	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV000756888	SCV003505745	uncertain significance	not provided	2022-08-23	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 4455 of the USH2A protein (p.Thr4455Ile). This variant is present in population databases (rs373152283, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with USH2A-related conditions. ClinVar contains an entry for this variant (Variation ID: 618475). 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 tolerated. 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	RCV003453540	SCV004181874	uncertain significance	Retinitis pigmentosa 39	2023-11-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001272943	SCV004181875	uncertain significance	Usher syndrome type 2A	2023-11-04	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000756888	SCV005187231	uncertain significance	not provided		criteria provided, single submitter	not provided
Natera, Inc.	RCV001272943	SCV001455394	uncertain significance	Usher syndrome type 2A	2019-11-11	no assertion criteria provided	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004817967	SCV005068910	uncertain significance	Retinal dystrophy	2022-01-01	no assertion criteria provided	clinical testing