ClinVar Miner

Submissions for variant NM_033056.4(PCDH15):c.7C>T (p.Arg3Ter) (rs137853001)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000005216 SCV000220958 likely pathogenic Usher syndrome type 1F 2014-12-15 criteria provided, single submitter literature only
Integrated Genetics/Laboratory Corporation of America RCV000005216 SCV000699764 pathogenic Usher syndrome type 1F 2017-06-15 criteria provided, single submitter clinical testing Variant summary: The PCDH15 c.7C>T (p.Arg3X) variant results in a premature termination codon, predicted to cause a truncated or absent PCDH15 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One truncation downstream of this position have been classified as pathogenic by our laboratory (e.g. c.733C>T, p.Arg245X). One in silico tool predicts a damaging outcome for this variant. This variant was found in 1/108974 control chromosomes at a frequency of 0.0000092, which does not exceed the estimated maximal expected allele frequency of a pathogenic PCDH15 variant (0.0031623). This variant has been reported in multiple studies in patients with USH syndrome, in both homozygotes and heterozygotes (Ahmed_AJHG_2001, Jaijo_BMB_2010, Roux_Invest Ophthalmol Vis Sci_2011), with the UMD-PCDH15 database reporting this variant in 14 patients. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000824737 SCV000710846 pathogenic Rare genetic deafness 2017-02-07 criteria provided, single submitter clinical testing The p.Arg3X variant in PCDH15 has been reported in 10 individuals with Usher syn drome (including 7 homozygous and 1 compound heterozygous) and segregated with d isease in 10 affected relatives from 2 families (Alagramam 2001, Roux 2011, Ahme d 2008, Ahmed 2001, Aparisi 2014, Bonnet 2016, Jaijo 2009, Perreault-Micale 2014 ). This variant has been identified in (1/14512) of Asian chromosomes by the Exo me Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs1378530 01); however, this low frequency in the general population is consistent with th e carrier frequency for recessive hearing loss. This nonsense variant leads to a premature termination codon at position 3, which is predicted to lead to a trun cated or absent protein. Loss of PCDH15 function is an established disease mecha nism for Usher syndrome. In summary, this variant meets criteria to be classifie d as pathogenic for autosomal recessive Usher syndrome based on its presence in the homozygous or compound heterozygous state in multiple affected individuals, segregation with disease in multiple affected relatives, extremely low frequency in the general population, and its predicted impact on the protein.
Invitae RCV000808283 SCV000948385 pathogenic not provided 2018-07-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg3*) in the PCDH15 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs137853001, ExAC 0.007%). This variant has been observed to be homozygous or in combination with another PCDH15 variant in several individuals affected with Usher syndrome (PMID: 11487575, 25404053, 27440999, 27460420). ClinVar contains an entry for this variant (Variation ID: 4931). Loss-of-function variants in PCDH15 are known to be pathogenic (PMID: 11398101, 11487575, 14570705). For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000808283 SCV001250219 pathogenic not provided 2016-10-01 criteria provided, single submitter clinical testing
OMIM RCV000005216 SCV000025394 pathogenic Usher syndrome type 1F 2001-07-01 no assertion criteria provided literature only
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery,Institute of Otolaryngology, Chinese PLA General Hospital RCV000770851 SCV000902353 pathogenic Deafness, autosomal recessive 23 2019-02-26 no assertion criteria provided case-control

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