ClinVar Miner

Submissions for variant NM_001384140.1(PCDH15):c.1784+1G>T

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV002789953 SCV003761073 likely pathogenic Usher syndrome type 1F 2023-01-24 criteria provided, single submitter curation The c.1784+1G>T variant in PCDH15 has been reported in 1 individual with Usher syndrome type 1F (PMID: 33946315) and has been identified in 0.005% (1/18340) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs761865629). 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).
Labcorp Genetics (formerly Invitae), Labcorp RCV005099229 SCV005781724 pathogenic not provided 2024-08-31 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 14 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 (rs761865629, gnomAD 0.006%). Disruption of this splice site has been observed in individual(s) with PCDH15-related conditions (PMID: 33946315; internal data). ClinVar contains an entry for this variant (Variation ID: 2412661). 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.
Baylor Genetics RCV003475524 SCV004200856 likely pathogenic Autosomal recessive nonsyndromic hearing loss 23 2023-02-04 flagged submission clinical testing

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