ClinVar Miner

Submissions for variant NM_001384140.1(PCDH15):c.2419dup (p.Ile807fs)

gnomAD frequency: 0.00001  dbSNP: rs781148814
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000412083 SCV000486501 likely pathogenic Usher syndrome type 1F 2016-06-21 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000824732 SCV000713303 pathogenic Rare genetic deafness 2017-07-10 criteria provided, single submitter clinical testing The p.Ile807fs variant in PCDH15 has not been previously reported in the literat ure, but has been reported in ClinVar (Variation ID: 371039). This variant has b een identified in 2/111580 European chromosomes by the Genome Aggregation Databa se (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs781148814). This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequen ce beginning at position 807 and leads to a premature termination codon 7 amino acids downstream. Loss of function of the PCDH15 gene is an established disease mechanism in autosomal recessive Usher syndrome type 1. In summary, this varian t meets criteria to be classified as pathogenic for Usher syndrome type 1 in an autosomal recessive manner based on predicted impact to the protein.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV000412083 SCV003761067 pathogenic Usher syndrome type 1F 2023-01-24 criteria provided, single submitter curation The p.Ile807fs variant in PCDH15 has been reported in 1 individual, in the compound heterozygous state, with Usher syndrome type 1F (internal data) and has been identified in 0.002% (2/113638) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs781148814). 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 predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 807 and leads to a premature termination codon 7 amino acids downstream. This alteration is then 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).

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