ClinVar Miner

Submissions for variant NM_001384140.1(PCDH15):c.3122+1G>T

gnomAD frequency: 0.00001  dbSNP: rs982893820
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001972905 SCV002249903 likely pathogenic not provided 2023-04-28 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 23 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 (no rsID available, gnomAD 0.007%). Disruption of this splice site has been observed in individual(s) with Usher syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 1468970). 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, Broad Institute of MIT and Harvard RCV002571248 SCV003761057 likely pathogenic Usher syndrome type 1F 2023-01-24 criteria provided, single submitter curation The c.3122+1G>T variant in PCDH15 has not been previously reported in individuals with Usher syndrome type 1F, and has been identified in 0.006% (1/15428) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs982893820). 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 is located in the 3' splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. Loss of function of the PCDH15 gene is an established disease mechanism in autosomal recessive Usher syndrome type 1F. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive Usher syndrome type 1F. ACMG/AMP Criteria applied: PVS1, PM2 (Richards 2015).

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