Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001240530 | SCV001413481 | likely pathogenic | not provided | 2024-08-20 | criteria provided, single submitter | clinical testing | This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 3666 of the USH2A protein (p.Cys3666Gly). This variant is present in population databases (rs766505885, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of USH2A-related conditions, retinitis pigmentosa, and/or Usher syndrome (PMID: 27208204, 35266249; internal data). ClinVar contains an entry for this variant (Variation ID: 236531). 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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Institute of Human Genetics, |
RCV000225467 | SCV005069833 | likely pathogenic | Retinal dystrophy | 2019-01-01 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV004767180 | SCV005381226 | uncertain significance | not specified | 2024-08-07 | criteria provided, single submitter | clinical testing | Variant summary: USH2A c.10996T>G (p.Cys3666Gly) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Four 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 251436 control chromosomes (gnomAD). c.10996T>G has been reported in the literature in individuals affected with Retinal Disease (e.g. Ellingford_2016, Lin_2024). 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: 27208204, 35266249, 38219857, 31998945, 33749171). ClinVar contains an entry for this variant (Variation ID: 236531). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |
| Centre for Genomic Medicine, |
RCV000225467 | SCV000282641 | uncertain significance | Retinal dystrophy | no assertion criteria provided | clinical testing |