Submissions for variant NM_033056.4(PCDH15):c.5598AAC[1] (p.Thr1869del)

dbSNP: rs113363047

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000039764	SCV000063453	benign	not specified	2011-09-17	criteria provided, single submitter	clinical testing	Thr1869del in exon 33 of PCDH15: This variant has been reported in 4 individuals with Usher syndrome and one individual with hearing loss, and was absent in 100 control chromosomes (Ouyang 2005, Zheng 2005, Bonnet 2011). However, three of t he Usher syndrome probands did not have a second PCDH15 variant identified, incl uding two probands who had pathogenic variants in another gene. The fourth Usher syndrome proband carried the variant in the compound heterozygous state with an other PCDH15 variant which we feel does not have evidence for pathogenicity. The proband with hearing loss carried this variant in the homozygous state; this is inconsistent with the phenotype expected of two pathogenic PCDH15 variants. Thi s variant has also been identified by our laboratory in two probands, both of wh om carry pathogenic or likely pathogenic variants in other genes. Furthermore, G ET-Evidence database (http://evidence.personalgenomes.org) reports this variant at a frequency of 6% (8/128 chromosomes). In summary, based upon the observation s to date, we feel this variant is likely benign.
Eurofins Ntd Llc (ga)	RCV000039764	SCV000203200	benign	not specified	2013-12-17	criteria provided, single submitter	clinical testing
GeneDx	RCV000039764	SCV000565362	benign	not specified	2016-06-22	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000514811	SCV000609994	benign	not provided	2017-02-24	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000514811	SCV001110665	benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000514811	SCV001144885	benign	not provided	2018-11-12	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000514811	SCV001159101	benign	not provided	2023-11-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000039764	SCV001623345	benign	not specified	2021-04-18	criteria provided, single submitter	clinical testing	Variant summary: PCDH15 c.5601_5603delAAC (p.Thr1869del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 0.0072 in 251400 control chromosomes, predominantly at a frequency of 0.088 within the African or African-American subpopulation in the gnomAD database, including 72 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 28 fold of the estimated maximal expected allele frequency for a pathogenic variant in PCDH15 causing Usher Syndrome Type 1F phenotype (0.0032), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Although cited in the literature, to our knowledge, no occurrence of c.5601_5603delAAC in individuals affected with Usher Syndrome Type 1F and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all submitters classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
Fulgent Genetics, Fulgent Genetics	RCV002490550	SCV002804175	benign	Autosomal recessive nonsyndromic hearing loss 23; Usher syndrome type 1D; Usher syndrome type 1F	2022-04-04	criteria provided, single submitter	clinical testing
OMIM	RCV001272395	SCV000025397	pathogenic	Usher syndrome type 1F	2005-03-01	no assertion criteria provided	literature only
OMIM	RCV002277128	SCV000025398	pathogenic	USHER SYNDROME, TYPE ID/F, DIGENIC	2005-03-01	no assertion criteria provided	literature only
GeneReviews	RCV000215699	SCV000268760	not provided	Usher syndrome type 1		no assertion provided	literature only
Natera, Inc.	RCV001272395	SCV001454379	benign	Usher syndrome type 1F	2020-04-13	no assertion criteria provided	clinical testing