ClinVar Miner

Submissions for variant NM_001384140.1(PCDH15):c.4211+2T>G

gnomAD frequency: 0.00001  dbSNP: rs753832779
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000667757 SCV000792257 likely pathogenic Usher syndrome type 1F 2017-06-13 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000793173 SCV000932514 likely pathogenic not provided 2024-02-23 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 31 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 (rs753832779, 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: 552486). 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 RCV000667757 SCV003761039 uncertain significance Usher syndrome type 1F 2023-01-24 criteria provided, single submitter curation The c.4211+2T>G 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% (2/21636) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs753832779). 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#: 552486) and has been interpreted as likely pathogenic by Invitae and Counsyl. 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 that is 3 amino acids long, and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Furthermore, spliceAI predicts exon skipping of the adjacent exon with a high score. In summary, the clinical significance of the c.4211+2T>G variant is uncertain. ACMG/AMP Criteria applied: PM2_supporting, PVS1_moderate (Richards 2015).

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