Submissions for variant NM_033056.4(PCDH15):c.5347_5363del (p.Pro1783fs)

dbSNP: rs748086016

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000671747	SCV000796761	uncertain significance	Usher syndrome type 1F	2017-12-28	criteria provided, single submitter	clinical testing
GeneID Lab - Advanced Molecular Diagnostics	RCV000671747	SCV000807814	likely pathogenic	Usher syndrome type 1F	2018-03-10	criteria provided, single submitter	clinical testing	This variant results in an amino acid alteration replacing a proline (P) with a serine (S) at position 1783 creating a premature stop signal in the new reading frame noted as p.R80Pfs*69. The substitution is predicted to result in a non-functional PDCH15 protein, either through protein truncation or nonsense-mediated mRNA decay. This mutation is considered a non-tolerated amino acid change based on in silico prediction algorithms (disease causing), and it has not been reported in the ClinVar Database (NCBI National Library of Medicine, NIH, Bethesda MD), but it has been described in 12 alleles out of 50254, in the ExAC database, all of them belonging to heterozygous carries of Latino origin. Based on these findings and the limited literature regarding this substitution we consider it as a likely pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000961061	SCV001108090	likely benign	not provided	2024-01-22	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000961061	SCV002021623	likely pathogenic	not provided	2022-11-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004768541	SCV005381580	likely benign	not specified	2024-08-02	criteria provided, single submitter	clinical testing	Variant summary: PCDH15 c.5347_5363del17 (p.Pro1783SerfsX59) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00011 in 189612 control chromosomes in the gnomAD database, including 2 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in PCDH15 causing Usher Syndrome Type 1F (0.00011 vs 0.0032), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.5347_5363del17 in individuals affected with Usher Syndrome Type 1F and no experimental evidence demonstrating its impact on protein function have been reported. However, an upstream truncating variant NM_033056.4:c.4831_4834dup (p.Thr1612fs) has been universally classified as Likely Benign/Benign by at least 5 laboratories in ClinVar and has a gnomAD frequency of ~1% in the African/African American subpopulation, including 4 homozygotes. These data suggest the C-terminal region downstream of p.Thr1612 may be dispensable for PCDH15 function. ClinVar contains an entry for this variant (Variation ID: 555843). Based on the evidence outlined above, the variant was classified as likely benign.
Natera, Inc.	RCV000671747	SCV002075571	likely benign	Usher syndrome type 1F	2020-08-19	no assertion criteria provided	clinical testing