Submissions for variant NM_206933.4(USH2A):c.2332G>T (p.Asp778Tyr)

gnomAD frequency: 0.00015  dbSNP: rs142898216

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000155332	SCV000205018	uncertain significance	not specified	2014-11-07	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Asp778Tyr variant in USH2A has been reported in 1 Spanish individual with Usher syndrome who also carried a known pathogenic variant (Aller 2006). This variant has been identified in 0.05% (2/4406) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs142898216); howev er this frequency is not high enough to rule out a pathogenic role. Computationa l prediction tools suggest that the p.Asp778Tyr variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical signi ficance of the p.Asp778Tyr variant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001051381	SCV001215533	pathogenic	not provided	2023-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 778 of the USH2A protein (p.Asp778Tyr). This variant is present in population databases (rs142898216, gnomAD 0.05%). This missense change has been observed in individual(s) with Usher syndrome or non-syndromic retinal disease (PMID: 17085681, 25649381, 26969326; Invitae). 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: 178583). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt USH2A protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001073261	SCV001238797	pathogenic	Retinal dystrophy	2018-09-26	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001051381	SCV001248857	pathogenic	not provided	2017-05-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001051381	SCV001802507	uncertain significance	not provided	2021-04-06	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31904091, 31736247, 17085681, 26969326, 32637036, 25649381)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001051381	SCV002048766	uncertain significance	not provided	2021-04-13	criteria provided, single submitter	clinical testing	The USH2A c.2332G>T; p.Asp778Tyr variant (rs142898216; ClinVar Variation ID: 178583) has been previously observed in patients with clinical features of Usher syndrome (US) or retinitis pigmentosa (RP). One patient with US found to be homozygous for this variant, while one US and one RP patient were found to carry this variant in a presumed transheterozygous configuration with other established pathogenic variants in USH2A (Aller 2006, Lenassi 2015, Sloan-Heggen 2016). This variants is rare in the general population, though it is found at higher frequencies is African Americans in in the Genome Aggregation Database (0.056% MAF; 14 out of 24,968 chromosomes, including 1 homozygous individual). The aspartic acid at codon 778 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.598). Based on the available information, the clinical significance of this variant is uncertain. References: Aller et al. Identification of 14 novel mutations in the long isoform of USH2A in Spanish patients with Usher syndrome type II. J Med Genet. 2006 Nov;43(11):e55. PMID: 17085681 Lenassi et al. A detailed clinical and molecular survey of subjects with nonsyndromic USH2A retinopathy reveals an allelic hierarchy of disease-causing variants. Eur J Hum Genet. 2015 Oct;23(10):1318-27. PMID: 25649381 Sloan-Heggen et al. Comprehensive genetic testing in the clinical evaluation of 1119 patients with hearing loss. Hum Genet. 2016 Apr;135(4):441-450. PMID: 26969326
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001804867	SCV002051125	pathogenic	Usher syndrome	2021-12-14	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.2332G>T (p.Asp778Tyr) results in a non-conservative amino acid change located in the Laminin-type EGF domain (IPR002049) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 250894 control chromosomes in the gnomAD database, including 1 homozygote. c.2332G>T has been reported in the literature in multiple compound heterozygous individuals affected with Usher Syndrome or retinal disease (examples: Aller_2006, Sloan-Heggen_2016, Zenteno_2019, and McGowan_2020), as well as a homozygous individual with normal hearing and nyctalopia (Lenassi_2015). These data indicate that the variant is very likely to be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=3) and as a variant of uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc.	RCV001810429	SCV002060086	uncertain significance	Usher syndrome type 2A	2021-11-03	criteria provided, single submitter	clinical testing	NM_206933.2(USH2A):c.2332G>T(D778Y) is a missense variant classified as a variant of uncertain significance in the context of USH2A-related disorders. D778Y has been observed in cases with relevant disease (PMID: 31736247, 25649381, 17085681, 26969326). Functional assessments of this variant are not available in the literature. D778Y has been observed in population frequency databases (gnomAD: AFR 0.05%). In summary, there is insufficient evidence to classify NM_206933.2(USH2A):c.2332G>T(D778Y) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.