Submissions for variant NM_206933.4(USH2A):c.14017T>C (p.Tyr4673His)

gnomAD frequency: 0.00001  dbSNP: rs1040917329

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Myriad Genetics, Inc.	RCV001810480	SCV002060331	uncertain significance	Usher syndrome type 2A	2021-10-01	criteria provided, single submitter	clinical testing	NM_206933.2(USH2A):c.14017T>C(Y4673H) is a missense variant classified as a variant of uncertain significance in the context of USH2A-related disorders. Y4673H has been observed in cases with relevant disease (PMID: 26992781, 25373420, 24853665, 26927203, 23967202). Functional assessments of this variant are not available in the literature. Y4673H has been observed in population frequency databases (gnomAD: EAS 0.02%). In summary, there is insufficient evidence to classify NM_206933.2(USH2A):c.14017T>C(Y4673H) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271562	SCV002556308	uncertain significance	not specified	2022-06-02	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.14017T>C (p.Tyr4673His) results in a conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251322 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.14017T>C has been reported in the literature in individuals affected with deafness, Retinitis Pigmentosa, or retinal degeneration. These data do not allow any conclusion about variant significance. 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 without evidence for independent evaluation. Both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002531342	SCV003523650	uncertain significance	not provided	2022-03-29	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 4673 of the USH2A protein (p.Tyr4673His). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with USH2A-related conditions (PMID: 25373420, 26992781, 30948794, 31054281, 32188678, 32675063, 32893482, 33090715). 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: 557599). 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 disruptive. 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	RCV003453366	SCV004183108	uncertain significance	Retinitis pigmentosa 39	2023-11-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001810480	SCV004183109	uncertain significance	Usher syndrome type 2A	2023-11-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003453366	SCV004207703	uncertain significance	Retinitis pigmentosa 39	2024-03-25	criteria provided, single submitter	clinical testing
Dept Of Ophthalmology, Nagoya University	RCV003889962	SCV004707222	uncertain significance	Retinal dystrophy	2023-10-01	criteria provided, single submitter	research
PreventionGenetics, part of Exact Sciences	RCV004732997	SCV005347465	uncertain significance	USH2A-related disorder	2024-08-27	no assertion criteria provided	clinical testing	The USH2A c.14017T>C variant is predicted to result in the amino acid substitution p.Tyr4673His. This variant has been reported in multiple individuals with symptoms of Usher syndrome (see for example, Miyagawa et al. 2013. PubMed ID: 23967202; Chen et al. 2020. PubMed ID: 32893482; Liu et al. 2020. PubMed ID: 33090715). This variant is reported in 0.015% of alleles in individuals of East Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.