Submissions for variant NM_206933.4(USH2A):c.4616C>T (p.Thr1539Ile)

gnomAD frequency: 0.00001  dbSNP: rs758095361

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV001073769	SCV001239329	uncertain significance	Retinal dystrophy	2017-12-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001731858	SCV001983722	likely pathogenic	Usher syndrome	2021-09-27	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.4616C>T (p.Thr1539Ile) results in a non-conservative amino acid change located in the Laminin G domain (IPR001791) 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 6.4e-05 in 250428 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (6.4e-05 vs 0.011), allowing no conclusion about variant significance. c.4616C>T has been reported in the literature in well-genotyped cohorts of East Asian origin (WES and large NGS panels) as a compound heterozygous genotype in a family with Leber congenital amaurosis (LCA) (Chen_2013), Usher syndrome (Wang_2018) and Retinitis Pigmentosa (Dan_2020), as a homozygous genotype in a patient with Retinitis Pigmentosa (Gao_2021), and as a non-informative genotype (second variant not specified) in a patient with deafness, Retinitis pigmentosa (RP) and Usher syndrome (Miyagawa_2013, Katagiri_2014, Sun_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 (evaluated in 2017) without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. One submitter cites overlapping but not all the recently published evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Myriad Genetics, Inc.	RCV001810466	SCV002060346	uncertain significance	Usher syndrome type 2A	2021-11-11	criteria provided, single submitter	clinical testing	NM_206933.2(USH2A):c.4616C>T(T1539I) is a missense variant classified as a variant of uncertain significance in the context of USH2A-related disorders. T1539I has been observed in cases with relevant disease (PMID: 23967202, 30029497, 29625443, 25268133, 32188678, 31960602, 31213501). Functional assessments of this variant are not available in the literature. T1539I has been observed in population frequency databases (gnomAD: EAS 0.09%). In summary, there is insufficient evidence to classify NM_206933.2(USH2A):c.4616C>T(T1539I) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002530650	SCV003523616	uncertain significance	not provided	2022-04-12	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 1539 of the USH2A protein (p.Thr1539Ile). This variant is present in population databases (rs758095361, gnomAD 0.09%). This missense change has been observed in individuals with retinitis pigmentosa and/or Usher syndrome (PMID: 23967202, 29625443, 30029497, 31960602, 32188678). ClinVar contains an entry for this variant (Variation ID: 550482). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Baylor Genetics	RCV003459568	SCV004208144	likely pathogenic	Retinitis pigmentosa 39	2024-03-24	criteria provided, single submitter	clinical testing
Dept Of Ophthalmology, Nagoya University	RCV001073769	SCV004708005	uncertain significance	Retinal dystrophy	2023-10-01	criteria provided, single submitter	research
Fulgent Genetics, Fulgent Genetics	RCV005019103	SCV005638236	likely pathogenic	Usher syndrome type 2A; Retinitis pigmentosa 39	2024-01-24	criteria provided, single submitter	clinical testing