Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000710333 | SCV000840526 | likely pathogenic | Usher syndrome | 2023-09-26 | reviewed by expert panel | curation | The variant NM_206933.3:c.12295-?_14133+?del in USH2A is an in-frame multi-exon deletion that leads to a truncation of a functionally important region in a gene where loss-of-function is an established disease mechanism (PVS1_Strong). The variant is absent from gnomAD v2.1.1 (PM2_Supporting). It has been detected as homozygous in one proband with Usher syndrome, as compound heterozygous with p.Arg334Gly in one proband with hearing loss and light sensitivity, and as compound heterozygous with p.Tyr3747Ter in one proband with hearing loss (PM3; Partners LMM internal data SCV000204167.4). At least one patient with a variant in this gene displayed features of moderate to severe hearing loss and retinitis pigmentosa (PP4; Partners LMM internal data SCV000204167.4). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PVS1_Strong, PM2_Supporting, PM3, PP4 (ClinGen Hearing Loss VCEP specifications version 2; 9/26/2023). |
| Laboratory for Molecular Medicine, |
RCV000154497 | SCV000204167 | pathogenic | Rare genetic deafness | 2017-03-11 | criteria provided, single submitter | clinical testing | The deletion encompassing exons 63 and 64 of USH2A has been identified by our la boratory in 1 individual with Usher syndrome who was homozygous for the deletion , and in 1 young individual with hearing loss who was heterozygous for the delet ion as well as a suspect variant of uncertain significance in USH2A. It has also been reported in 1 young proband (<10yrs) with hearing loss, who carried a seco nd suspicious variant in USH2A (Sloan-Heggen 2016). This variant has been report ed in 1/5083 African chromosomes by the Exome Aggregation Consortium (ExAC, http ://exac.broadinstitute.org), which is consistent with a recessive carrier freque ncy. The deletion of exons 63-64 is predicted to result in an in-frame deletion that removes >10% of the protein. Therefore, this deletion would result in eithe r a truncated or absent protein, which is expected to disrupt protein function. In addition, given that previous individuals with this deletion did not carry th e p.Tyr3747X variant that was detected in this individual, it's probable that th e variants are in trans, which further supports a causative role for the two va riants. In summary, this variant meets our criteria to be classified as pathogen ic for autosomal recessive Usher syndrome. ACMG/AMP criteria applied: PVS1; PM2; PM3; PP4. |
| Invitae | RCV001031135 | SCV001194441 | pathogenic | not provided | 2019-12-19 | criteria provided, single submitter | clinical testing | This variant is an in-frame deletion of the genomic region encompassing exons 63-64 of the USH2A gene. It preserves the integrity of the reading frame. Deletions of exons 63-64 have been observed in individuals affected with clinical features of retinitis pigmentosa and/or hearing loss (PMID: 28041643, 26969326, Invitae). This variant disrupts the p.Thr4439 amino acid residue in USH2A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25521520, 22135276, 27460420). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |