Submissions for variant NM_206933.4(USH2A):c.13547G>C (p.Gly4516Ala)

gnomAD frequency: 0.00001  dbSNP: rs774759345

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000594966	SCV000704113	uncertain significance	not provided	2018-06-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000594966	SCV001785237	uncertain significance	not provided	2021-09-24	criteria provided, single submitter	clinical testing	Observed in a patient with Usher syndrome in published literature who had a second variant in USH2A, although additional clinical information and segregation data were not provided (Dedania et al., 2017); Not observed at significant frequency in large population cohorts (Lek et al., 2016); 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: 28704108)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000594966	SCV002265261	pathogenic	not provided	2022-08-07	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly4516 amino acid residue in USH2A. Other variant(s) that disrupt this residue have been observed in individuals with USH2A-related conditions (PMID: 28127548), which suggests that this may be a clinically significant amino acid residue. 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. ClinVar contains an entry for this variant (Variation ID: 498883). This missense change has been observed in individual(s) with clinical features of USH2A-related conditions (PMID: 28704108; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 4516 of the USH2A protein (p.Gly4516Ala).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987614	SCV004804492	uncertain significance	not specified	2024-01-11	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.13547G>C (p.Gly4516Ala) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250978 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.13547G>C has been reported in the literature in at least one individual affected with retinal dystrophy, specifically an Usher phenotype (e.g. Dedania_2018). Although it was reported in compound heterozygosity with another variant (p.Gly1132Asp), this second variant has conflicting evidence for pathogenicity in ClinVar, with the most severe classification being VUS and most submitters classifying it as benign/likely benign. Therefore, this report does not provide unequivocal conclusions about association of the p.Gly4516Ala variant with Usher Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 28704108). ClinVar contains an entry for this variant (Variation ID: 498883). Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV001834880	SCV002088253	uncertain significance	Usher syndrome type 2A	2021-06-25	no assertion criteria provided	clinical testing