Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001049950 | SCV001214033 | pathogenic | not provided | 2024-01-22 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 4032 of the USH2A protein (p.Gly4032Arg). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individuals with Usher syndrome or retinitis pigmentosa (PMID: 26667666, 27460420, 29847639, 33105608; Invitae). ClinVar contains an entry for this variant (Variation ID: 846609). 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%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Gly4032 amino acid residue in USH2A. Other variant(s) that disrupt this residue have been observed in individuals with USH2A-related conditions (PMID: 27208204), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003396663 | SCV004122661 | uncertain significance | not specified | 2023-10-09 | criteria provided, single submitter | clinical testing | Variant summary: USH2A c.12094G>A (p.Gly4032Arg) 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 allele was found at a frequency of 4e-06 in 250584 control chromosomes (gnomAD). c.12094G>A has been reported in the literature in individuals affected with Usher syndrome or retinitis pigmentosa (examples: Ge_2015, Bonnet_2016, Martin-Merida_2018, Fakin_2019, Inaba_2020, Numa_2020, Schlottmann_2023). These data indicate that the variant may 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: 27460420, 31766479, 26667666, 33105608, 29847639, 37217489, 33247286). A different variant affecting the same codon has been reported in at-least one patient affected with Usher syndrome (PMID: 33247286) and has been classified pathogenic in ClinVar (CV ID 236540). However this information is not sufficient to conclusively associate c.12094G>A (p.Gly4032Arg) variant with the disease. One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |
| Baylor Genetics | RCV003462545 | SCV004206321 | pathogenic | Retinitis pigmentosa 39 | 2023-02-21 | criteria provided, single submitter | clinical testing |