ClinVar Miner

Submissions for variant NM_033056.4(PCDH15):c.3441dup (p.Phe1148fs) (rs770832663)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000409226 SCV000485345 likely pathogenic Usher syndrome, type 1F 2015-11-24 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000826148 SCV000967679 pathogenic Rare genetic deafness 2018-03-02 criteria provided, single submitter clinical testing The p.Phe1148fs variant in PCDH15 has been reported in one individual with Usher syndrome, who was compound heterozygous with a second likely pathogenic PCDH15 variant (Lenarduzzi 2015). This variant has been identified in 1/111386 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinst itute.org/; dbSNP rs770832663) and has been reported in ClinVar (Variation ID: 3 70113). Although this variant has been seen in the general population, its frequ ency is low enough to be consistent with a recessive carrier frequency. This var iant is predicted to cause a frameshift, which alters the protein?s amino acid s equence beginning at position 1148 and leads to a premature termination codon 8 amino acids downstream. Loss of PCDH15 function is an established disease mechan ism for Usher syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome based on its presence in a n affected individual, extremely low frequency in the general population, and it s predicted impact on the protein. ACMG/AMP Criteria applied: PVS1; PM2; PM3; PP 4.

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