Submissions for variant NM_206933.4(USH2A):c.2653C>T (p.His885Tyr)

gnomAD frequency: 0.00002  dbSNP: rs746071929

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000778220	SCV000914386	uncertain significance	Retinitis pigmentosa	2019-01-10	criteria provided, single submitter	clinical testing	The USH2A c.2653C>T (p.His885Tyr) missense variant has been reported in two studies in which it is found in a total of three individuals with retinitis pigmentosa. The variant was identified in two of these individuals in a compound heterozygous state with a second splice site variant (Xu et al. 2014). The third individual carried two previously reported missense variants in addition to the p.His885Tyr variant, the phase of which were not given (Oishi et al. 2014). The p.His885Tyr variant was absent from 96 controls but is reported at a frequency of 0.00081 in the East Asian population of the Exome Aggregation Consortium. Based on the evidence, the USH2 p.His885Tyr variant is classified as a variant of unknown significance but suspicious for pathogenicity for autosomal recessive retinitis pigmentosa. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Blueprint Genetics	RCV001075434	SCV001241057	uncertain significance	Retinal dystrophy	2018-08-27	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001098933	SCV001255334	uncertain significance	Usher syndrome type 2A	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001244238	SCV001417444	pathogenic	not provided	2024-11-02	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 885 of the USH2A protein (p.His885Tyr). This variant is present in population databases (rs746071929, gnomAD 0.07%). This missense change has been observed in individual(s) with clinical features of Usher syndrome and/or retinitis pigmentosa (PMID: 24938718, 32188678, 33105608, 33111992). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 550419). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on USH2A protein function. For these reasons, this variant has been classified as Pathogenic.
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV001376385	SCV001573505	uncertain significance	Retinitis pigmentosa 39	2021-04-08	criteria provided, single submitter	research	The USH2A c.2653C>T variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2. Based on this evidence we have classified this variant as Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001731856	SCV001983721	uncertain significance	not specified	2021-09-27	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.2653C>T (p.His885Tyr) results in a conservative amino acid change located in the Laminin EGF domain (IPR002049) 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 4.8e-05 in 250902 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in USH2A causing Usher Syndrome (4.8e-05 vs 0.011), allowing no conclusion about variant significance. c.2653C>T has been reported in the literature predominantly in East Asian cohorts as a compound heterozygous genotype in two patients with Retinitis pigmentosa (Xu_2014) and a patient with non-syndromic sensorineural hearing loss but no retinal changes (Brodie_2021). It has also been reported as a non-informative genotype (with more than two USH2A variants and phase not specified) in patients with Usher (Ooshi_2014) and Retinitis Pigmentosa (Inaba_2020, Gao_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six 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 VUS-possibly pathogenic.
Myriad Genetics, Inc.	RCV001098933	SCV002060364	uncertain significance	Usher syndrome type 2A	2021-11-03	criteria provided, single submitter	clinical testing	NM_206933.2(USH2A):c.2653C>T(H885Y) is a missense variant classified as a variant of uncertain significance in the context of USH2A-related disorders. H885Y has been observed in cases with relevant disease (PMID: 25324289, 24938718, 33111992, 33105608, 32188678). Functional assessments of this variant are not available in the literature. H885Y has been observed in population frequency databases (gnomAD: EAS 0.07%). In summary, there is insufficient evidence to classify NM_206933.2(USH2A):c.2653C>T(H885Y) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
GeneDx	RCV001244238	SCV002538807	likely pathogenic	not provided	2024-07-24	criteria provided, single submitter	clinical testing	Reported with two or more USH2A variants in patients in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in all cases (PMID: 25324289, 33105608, 32188678); 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: 33111992, 24938718, 31054281, 25324289, 33105608, 32188678, 31964843, 34515852, 34906470, 38879497)
Baylor Genetics	RCV001376385	SCV004200684	uncertain significance	Retinitis pigmentosa 39	2023-06-09	criteria provided, single submitter	clinical testing
Dept Of Ophthalmology, Nagoya University	RCV001075434	SCV004708034	uncertain significance	Retinal dystrophy	2023-10-01	criteria provided, single submitter	research
Fulgent Genetics, Fulgent Genetics	RCV005010648	SCV005643474	likely pathogenic	Usher syndrome type 2A; Retinitis pigmentosa 39	2024-06-11	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001098933	SCV002093948	uncertain significance	Usher syndrome type 2A	2020-02-06	no assertion criteria provided	clinical testing