ClinVar Miner

Submissions for variant NM_001384140.1(PCDH15):c.1863_1864dup (p.Ser622fs)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV003062260 SCV003441641 pathogenic not provided 2023-06-19 criteria provided, single submitter clinical testing This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with PCDH15-related conditions (PMID: 26166082, 30029497). For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Ser622Ilefs*9) in the PCDH15 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PCDH15 are known to be pathogenic (PMID: 11398101, 11487575, 14570705).
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV003062261 SCV003761071 pathogenic Usher syndrome type 1F 2023-01-24 criteria provided, single submitter curation The p.Ser622fs variant in PCDH15 has been reported in 3 individuals with Usher syndrome type 1F (PMID: 26166082, 30029497, 33724713) and has been identified in 0.005% (1/18338) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs764292129). 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. Of the 3 affected individuals, 2 of those were homozygotes, which increases the likelihood that the p.Ser622fs variant is pathogenic (PMID: 26166082, 30029497). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 622 and leads to a premature termination codon 9 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the PCDH15 gene is an established disease mechanism in autosomal recessive Usher syndrome type 1F. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome type 1F. ACMG/AMP Criteria applied: PVS1, PM2_supporting, PM3 (Richards 2015).
Baylor Genetics RCV003475489 SCV004200826 pathogenic Autosomal recessive nonsyndromic hearing loss 23 2023-05-12 flagged submission clinical testing

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