Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001324974 | SCV001515946 | likely pathogenic | not provided | 2023-10-19 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 5007 of the USH2A protein (p.Pro5007Leu). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with USH2A-related conditions (PMID: 27353947; Invitae). 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: 1024750). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on USH2A protein function. 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003331115 | SCV004037733 | uncertain significance | not specified | 2023-08-29 | criteria provided, single submitter | clinical testing | Variant summary: USH2A c.15020C>T (p.Pro5007Leu) results in a non-conservative amino acid change in 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 251406 control chromosomes (gnomAD). c.15020C>T has been reported in the literature in at least one individual affected with Retinitis Pigmentosa where it was confirmed to be in trans with a pathogenic variant (Tiwari_2016). 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. The following publication has been ascertained in the context of this evaluation (PMID: 27353947). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter, citing an internal observation, classified the variant as likely pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Natera, |
RCV001830997 | SCV002088203 | uncertain significance | Usher syndrome type 2A | 2020-09-22 | no assertion criteria provided | clinical testing |