ClinVar Miner

Submissions for variant NM_033056.4(PCDH15):c.4726C>T (p.Gln1576Ter)

dbSNP: rs758204385
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000669259 SCV000793994 uncertain significance Usher syndrome type 1F 2017-09-06 criteria provided, single submitter clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV000669259 SCV003761033 uncertain significance Usher syndrome type 1F 2023-01-24 criteria provided, single submitter curation The p.Gln1578Ter variant in PCDH15 has been reported in 7 individuals with Usher syndrome type 1F (PMID: 28281779, 32747562), segregated with disease in 10 affected relatives from 5 families (PMID: 28281779, 32747562), and has been identified in 0.003% (1/30614) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs758204385). 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#: 553746) and has been interpreted as a variant of uncertain significance by Counsyl. Of the 7 affected individuals, all of those were homozygotes, which increases the likelihood that the p.Gln1578Ter variant is pathogenic (PMID: 28281779, 32747562). This nonsense variant leads to a premature termination codon at position 1578. This variant is found in a region of PCDH15 that has limited evidence supporting an association with Usher syndrome type 1F (PMID: 25307757). In summary, the clinical significance of the p.Gln1578Ter variant is uncertain. ACMG/AMP Criteria applied: PP1_strong, PM3, PM2_supporting (Richards 2015).

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