Submissions for variant NM_001384140.1(PCDH15):c.7C>T (p.Arg3Ter)

gnomAD frequency: 0.00001  dbSNP: rs137853001

Total submissions: 13

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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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, Mass General Brigham 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000808283	SCV000948385	pathogenic	not provided	2022-11-23	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. Loss-of-function variants in PCDH15 are known to be pathogenic (PMID: 11398101, 11487575, 14570705). This variant is present in population databases (rs137853001, gnomAD 0.007%). This premature translational stop signal has been observed in individuals with Usher syndrome (PMID: 11487575, 25404053, 27440999, 27460420). ClinVar contains an entry for this variant (Variation ID: 4931). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000808283	SCV001250219	pathogenic	not provided	2016-10-01	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000005216	SCV003761098	pathogenic	Usher syndrome type 1F	2023-01-24	criteria provided, single submitter	curation	The p.Arg3Ter variant in PCDH15 has been reported in 4 individuals with Usher syndrome type 1F (PMID: 11487575, 18719945, 27460420, 31541171), segregated with disease in 5 affected relatives from 2 families (PMID: 18719945, 11487575), and has been identified in 0.007% (2/30248) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs137853001). 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#: 4931) and has been interpreted as pathogenic or likely pathogenic by multiple laboratories. Of the 4 affected individuals, 3 of those were homozygotes, which increases the likelihood that the p.Arg3Ter variant is pathogenic (PMID: 11487575, 18719945, 27460420). This nonsense variant leads to a premature termination codon at position 3, which is 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, PM3, PM2_supporting, PP1_strong (Richards 2015).
Baylor Genetics	RCV000770851	SCV004200775	pathogenic	Autosomal recessive nonsyndromic hearing loss 23	2024-02-06	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005041988	SCV005677285	pathogenic	Autosomal recessive nonsyndromic hearing loss 23; Usher syndrome type 1D; Usher syndrome type 1F	2024-01-02	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	Autosomal recessive nonsyndromic hearing loss 23	2019-02-26	no assertion criteria provided	case-control
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000808283	SCV001979530	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000808283	SCV001979949	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000005216	SCV002086092	pathogenic	Usher syndrome type 1F	2020-07-21	no assertion criteria provided	clinical testing