ClinVar Miner

Submissions for variant NM_033056.4(PCDH15):c.4462_4469dup (p.Glu1491fs) (rs774056663)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000498908 SCV000590716 likely pathogenic not provided 2017-06-14 criteria provided, single submitter clinical testing The c.4462_4469dupAATACTAT variant in the PCDH15 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.4462_4469dupAATACTAT variant causes a frameshift starting with codon Glutamic Acid 1491, changes this amino acid to an Isoleucine residue, and creates a premature Stop codon at position 11 of the new reading frame, denoted p.Glu1491IlefsX11. This variant is predicted to cause loss of normal protein function through protein truncation. The c.4462_4469dupAATACTAT variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.4462_4469dupAATACTAT as a likely pathogenic variant.
GeneID Lab - Advanced Molecular Diagnostics RCV000578273 SCV000680446 likely pathogenic Usher syndrome 2017-09-07 criteria provided, single submitter clinical testing
GeneID Lab - Advanced Molecular Diagnostics RCV000578330 SCV000680447 likely pathogenic Nonsyndromic Deafness 2017-09-07 criteria provided, single submitter clinical testing
Invitae RCV000498908 SCV001379388 pathogenic not provided 2020-04-26 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the PCDH15 gene (p.Glu1491Ilefs*11). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 465 amino acids of the PCDH15 protein. This variant is present in population databases (rs774056663, ExAC 0.003%). This variant has not been reported in the literature in individuals with PCDH15-related conditions. ClinVar contains an entry for this variant (Variation ID: 432938). This variant disrupts the C-terminus of the PCDH15 protein. Other variant(s) that disrupt this region (p.Gln1576*) have been determined to be pathogenic (PMID: 28281779). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

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