Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000781698 | SCV000919961 | pathogenic | Usher syndrome type 1F | 2018-03-02 | criteria provided, single submitter | clinical testing | Variant summary: PCDH15 c.2971C>T (p.Arg991X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2e-05 in 246060 control chromosomes. This frequency is not higher than expected for a pathogenic variant in PCDH15 causing Usher Syndrome Type 1F (2e-05 vs 0.0032), allowing no conclusion about variant significance. The c.2971C>T variant has been reported in the literature in multiple homozygous individuals affected with Usher Syndrome Type 1F. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Labcorp Genetics |
RCV001386497 | SCV001586741 | pathogenic | not provided | 2024-02-20 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Arg991*) in the PCDH15 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PCDH15 are known to be pathogenic (PMID: 11398101, 11487575, 14570705). This variant is present in population databases (rs754391973, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with clinical features of Usher syndrome (PMID: 16679490, 24618850, 29568747). It has also been observed to segregate with disease in related individuals. This variant is also known as c.2758C>T (p.R920*). ClinVar contains an entry for this variant (Variation ID: 224747). For these reasons, this variant has been classified as Pathogenic. |
| Broad Center for Mendelian Genomics, |
RCV000781698 | SCV003761059 | pathogenic | Usher syndrome type 1F | 2023-01-24 | criteria provided, single submitter | curation | The p.Arg991Ter variant in PCDH15 has been reported in at least 2 individuals with Usher syndrome type 1F (PMID: 16679490, 32531858), and has been identified in 0.004% (4/113468) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs754391973). 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#: 224747) and has been interpreted as pathogenic by Women's Health and Genetics/Laboratory Corporation of America (LabCorp), Invitae, and Centre for Genomic Medicine (Central Manchester University Hospitals). Of the 2 affected individuals, 1 was a compound heterozygote that carried a reported likely pathogenic variant in trans, which increases the likelihood that the p.Arg991Ter variant is pathogenic (PMID: 32531858). This nonsense variant leads to a premature termination codon at position 991, which is predicted to lead to a truncated or absent protein. Loss of function of the PCDH15 gene is an established disease mechanism in autosomal recessive Usher syndrome type 1F. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome type 1F. ACMG/AMP Criteria applied: PVS1, PM2_supporting, PM3 (Richards 2015). |
| Baylor Genetics | RCV003474992 | SCV004200781 | pathogenic | Autosomal recessive nonsyndromic hearing loss 23 | 2024-02-05 | criteria provided, single submitter | clinical testing | |
| Centre for Genomic Medicine, |
RCV000210315 | SCV000259086 | pathogenic | Usher syndrome type 1D | 2015-08-28 | no assertion criteria provided | clinical testing |