Submissions for variant NM_206933.4(USH2A):c.7787A>G (p.Tyr2596Cys)

gnomAD frequency: 0.00008  dbSNP: rs371685066

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001347814	SCV001542093	uncertain significance	not provided	2025-01-20	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 2596 of the USH2A protein (p.Tyr2596Cys). This variant is present in population databases (rs371685066, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of USH2A-related conditions (internal data). ClinVar contains an entry for this variant (Variation ID: 1043673). 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) indicates that this missense variant is expected to disrupt USH2A protein function with a positive predictive value of 95%. 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.
Ambry Genetics	RCV002547465	SCV003718737	uncertain significance	Inborn genetic diseases	2024-03-18	criteria provided, single submitter	clinical testing	The c.7787A>G (p.Y2596C) alteration is located in exon 41 (coding exon 40) of the USH2A gene. This alteration results from a A to G substitution at nucleotide position 7787, causing the tyrosine (Y) at amino acid position 2596 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV001347814	SCV003828086	uncertain significance	not provided	2020-03-04	criteria provided, single submitter	clinical testing
GeneDx	RCV001347814	SCV003845481	uncertain significance	not provided	2023-03-06	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Genome-Nilou Lab	RCV003449976	SCV004183198	uncertain significance	Retinitis pigmentosa 39	2023-11-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001831136	SCV004183199	uncertain significance	Usher syndrome type 2A	2023-11-04	criteria provided, single submitter	clinical testing
Dept Of Ophthalmology, Nagoya University	RCV003888051	SCV004707941	uncertain significance	Retinal dystrophy	2023-10-01	criteria provided, single submitter	research
Molecular Genetics, Royal Melbourne Hospital	RCV003994275	SCV004812519	uncertain significance	Usher syndrome type 2	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change in USH2A is predicted to replace tyrosine with cysteine at codon 2596, p.(Tyr2596Cys). The tyrosine residue is moderately conserved (100 vertebrates, Multiz alignments), and is located in the fibronectin type 3 domain. There is a large physicochemical difference between tyrosine and cysteine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.03% (7/24,956 alleles) in the African/African-American population, which is consistent with recessive disease. To our knowledge, this variant has not been previously reported in the relevant scientific literature. Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.897). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM2_Supporting, PP3
Natera, Inc.	RCV001831136	SCV002090843	uncertain significance	Usher syndrome type 2A	2019-11-06	no assertion criteria provided	clinical testing