Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Counsyl | RCV000410951 | SCV000486162 | likely pathogenic | Usher syndrome type 1F | 2016-04-08 | criteria provided, single submitter | clinical testing | |
| Institute of Medical Genetics and Applied Genomics, |
RCV001268370 | SCV001447253 | likely pathogenic | not provided | 2020-10-23 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV001268370 | SCV001586738 | pathogenic | not provided | 2022-02-04 | criteria provided, single submitter | clinical testing | Disruption of this splice site has been observed in individual(s) with Usher syndrome and profound hearing loss (PMID: 25575603, 28984810). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This sequence change affects a donor splice site in intron 29 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 (rs758921360, gnomAD 0.003%). This variant is also known as IVS30+1G>T and c.3998+1G>T. ClinVar contains an entry for this variant (Variation ID: 370764). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. |
| Broad Center for Mendelian Genomics, |
RCV000410951 | SCV003761043 | pathogenic | Usher syndrome type 1F | 2023-01-24 | criteria provided, single submitter | curation | The c.3983+1G>T variant in PCDH15 has been reported in 3 individuals with Usher syndrome type 1F (PMID: 25575603, 28984810, Kamenarova 2020) and has been identified in 0.003% (3/113732) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs758921360). 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#: 370764) and has been interpreted as pathogenic or likely pathogenic by Invitae, Institute of Medical Genetics and Applied Genomics (University Hospital Tübingen), and Counsyl. Of the 3 affected individuals, 1 of those was a homozygote, and 2 were compound heterozygotes that carried reported likely pathogenic variants in trans and with unknown phase, which increases the likelihood that the c.3983+1G>T variant is pathogenic (VariationID: 370113; PMID: 25575603, 28984810, Kamenarova 2020). This variant is located in the 3' splice region. Computational tools predict a splicing impact through intron retention, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome type 1F. ACMG/AMP Criteria applied: PVS1, PM3, PM2_supporting (Richards 2015). |
| Institute of Human Genetics, |
RCV004816632 | SCV005069006 | pathogenic | Retinal dystrophy | 2021-01-01 | no assertion criteria provided | clinical testing |