ClinVar Miner

Submissions for variant NM_001384140.1(PCDH15):c.4990dup (p.Met1664fs)

dbSNP: rs766484375
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000714884 SCV000845631 likely pathogenic Usher syndrome type 1F 2018-08-07 criteria provided, single submitter clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000714885 SCV000845632 likely pathogenic Autosomal recessive nonsyndromic hearing loss 23 2018-08-07 criteria provided, single submitter clinical testing
MGZ Medical Genetics Center RCV000714884 SCV002579846 likely pathogenic Usher syndrome type 1F 2021-12-13 criteria provided, single submitter clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV000714884 SCV003761101 uncertain significance Usher syndrome type 1F 2023-01-24 criteria provided, single submitter curation The p.Met1664fs variant in PCDH15 has not been previously reported in the literature in individuals with Usher syndrome type 1F but has been identified in 0.0009% (2/35372) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs766484375). 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#: 587635) and has been interpreted as likely pathogenic by Genomic Research Center (Shahid Beheshti University of Medical Sciences). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1664 and leads to a premature termination codon 18 amino acids downstream. This termination codon occurs within the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. In summary, the clinical significance of the p.Met1664fs variant is uncertain. ACMG/AMP Criteria applied: PM2_supporting, PVS1_moderate (Richards 2015).

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