Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Counsyl | RCV000668602 | SCV000793231 | likely pathogenic | Usher syndrome type 1F | 2017-08-07 | criteria provided, single submitter | clinical testing | |
| Laboratory for Molecular Medicine, |
RCV000826014 | SCV000967502 | uncertain significance | not specified | 2019-01-04 | criteria provided, single submitter | clinical testing | Variant classified as Uncertain Significance - Favor Pathogenic. The c.2751+2T>C variant in PCDH15 has not been previously reported in individuals with hearing loss or Usher syndrome, but has been identified in 0.009% (3/34484) of Latino ch romosomes by gnomAD (http://gnomad.broadinstitute.org). This variant occurs with in the canonical splice site (+/- 1,2). Although additional studies would be nee ded to determine its impact, this variant is predicted to cause altered splicing of exon 20. However, because a loss of exon 20 would preserve the protein readi ng frame, the biological impact of this variant is uncertain. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied: PM2_Supporting, PM4. |
| Labcorp Genetics |
RCV001855503 | SCV002288699 | likely pathogenic | not provided | 2024-01-04 | criteria provided, single submitter | clinical testing | This sequence change affects a donor splice site in intron 20 of the PCDH15 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PCDH15 are known to be pathogenic (PMID: 11398101, 11487575, 14570705). This variant is present in population databases (rs754543131, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with PCDH15-related conditions. ClinVar contains an entry for this variant (Variation ID: 553206). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. |
| Broad Center for Mendelian Genomics, |
RCV000668602 | SCV003761063 | uncertain significance | Usher syndrome type 1F | 2023-01-24 | criteria provided, single submitter | curation | The c.2751+2T>C variant in PCDH15 has not been previously reported in the literature in individuals with Usher syndrome type 1F but has been identified in 0.009% (3/34484) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs754543131). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 553206) and has been interpreted as likely pathogenic by Invitae and Counsyl and as a variant of uncertain significance by Laboratory for Molecular Medicine (Mass General Brigham Personalized Medicine). This variant is located in the 3' splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. This variant is adjacent to an in-frame exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. In summary, the clinical significance of the c.2751+2T>C variant is uncertain. ACMG/AMP Criteria applied: PM2_supporting, PVS1_moderate (Richards 2015). |
| Baylor Genetics | RCV003472103 | SCV004200770 | likely pathogenic | Autosomal recessive nonsyndromic hearing loss 23 | 2023-12-28 | criteria provided, single submitter | clinical testing |