ClinVar Miner

Submissions for variant NM_001384140.1(PCDH15):c.2868+5G>A

dbSNP: rs757993503
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001308843 SCV001498317 pathogenic not provided 2024-09-03 criteria provided, single submitter clinical testing This sequence change falls in intron 21 of the PCDH15 gene. It does not directly change the encoded amino acid sequence of the PCDH15 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs757993503, gnomAD 0.003%). This variant has been observed in individual(s) with clinical features of PCDH15-related conditions and/or Usher syndrome (PMID: 22815625, 32483926; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1011092). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant does not affect mRNA splicing (PMID: 23451239). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV002476424 SCV002780882 uncertain significance Autosomal recessive nonsyndromic hearing loss 23; Usher syndrome type 1D; Usher syndrome type 1F 2021-11-02 criteria provided, single submitter clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV001835512 SCV003761103 uncertain significance Usher syndrome type 1F 2023-01-24 criteria provided, single submitter curation The c.2868+5G>A variant in PCDH15 has been reported in 2 individuals with Usher syndrome type 1F (PMID: 22815625, 32483926) and has been identified in 0.003% (1/34582) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs757993503). 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#: 1011092) and has been interpreted as a variant of uncertain significance by Invitae and Natera, Inc.. Of the 2 affected individuals, 1 was a compound heterozygote that carried a reported pathogenic variant in trans, which increases the likelihood that the c.2868+5G>A variant is pathogenic (VariationID: 371411; PMID: 22815625). In vitro functional studies provide some evidence that the c.2868+5G>A variant may not impact protein function (PMID: 23451239). However, these types of assays may not accurately represent biological function This variant is located in the 3' splice region. Computational tools do suggest an impact to splicing. However, this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the c.2868+5G>A variant is uncertain. ACMG/AMP Criteria applied: PM3, BS3_supporting, PP3, PM2_supporting (Richards 2015).
Natera, Inc. RCV001835512 SCV002093123 uncertain significance Usher syndrome type 1F 2020-08-25 no assertion criteria provided clinical testing

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