ClinVar Miner

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

gnomAD frequency: 0.00003  dbSNP: rs774056663
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000498908 SCV000590716 likely pathogenic not provided 2022-06-21 criteria provided, single submitter clinical testing Frameshift variant predicted to result in protein truncation, as the last 465 amino acids are replaced with 10 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge
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 2024-01-25 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu1491Ilefs*11) in the PCDH15 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 465 amino acid(s) of the PCDH15 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 432938). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the PCDH15 protein in which other variant(s) (p.Gln1576*) have been determined to be pathogenic (PMID: 28281779). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV003476195 SCV004200846 uncertain significance Autosomal recessive nonsyndromic hearing loss 23 2023-02-28 criteria provided, single submitter clinical testing

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