Submissions for variant NM_206933.4(USH2A):c.820C>G (p.Arg274Gly)

dbSNP: rs397518036

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001360100	SCV001556000	pathogenic	not provided	2022-10-29	criteria provided, single submitter	clinical testing	This variant disrupts the p.Arg274 amino acid residue in USH2A. Other variant(s) that disrupt this residue have been observed in individuals with USH2A-related conditions (PMID: 27460420), 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: 438026). This missense change has been observed in individual(s) with clinical features of Usher syndrome (PMID: 28041643; Invitae). This variant is present in population databases (rs397518036, gnomAD 0.002%). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 274 of the USH2A protein (p.Arg274Gly). For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470889	SCV002766880	pathogenic	Usher syndrome type 2A	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Usher syndrome type 2A (MIM#276901). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glycine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (2 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (6 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated Concanavalin A-like lectin/glucanases superfamily domain (DECIPHER). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. p.(Arg274Gln) has been previously described as a variant of uncertain significance in multiple independent cases (ClinVar, PMIDs: 27460420, 28798898). (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic in an individual with Usher syndrome (PMID: 28041643). It has also been classified as a VUS by a clinical laboratory in ClinVar, however the description in the ClinVar entry is consistent with a variant of high clinical relevance. (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1201 - Heterozygous variant detected in trans with a pathogenic heterozygous variant (NM_206933.2(USH2A):c.1036A>C; p.(Asn346His)) in a recessive disease. (SP) 1206 - This variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Genome-Nilou Lab	RCV002470889	SCV004182946	pathogenic	Usher syndrome type 2A	2023-11-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000504853	SCV005885130	likely pathogenic	Usher syndrome	2024-12-18	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.820C>G (p.Arg274Gly) results in a non-conservative amino acid change in 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 8e-06 in 250882 control chromosomes (gnomAD). c.820C>G has been reported in the literature in individuals affected with Usher Syndrome or inherited retinal disease (Carss_2017, Panneman_2023, Lin_2024, Labcorp (formerly Invitae)). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28041643, 36819107, 38219857). ClinVar contains an entry for this variant (Variation ID: 438026). Based on the evidence outlined above, the variant was classified as likely pathogenic.
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504853	SCV000598830	likely pathogenic	Usher syndrome	2015-01-01	no assertion criteria provided	research