Submissions for variant NM_001384140.1(PCDH15):c.3817C>A (p.Arg1273Ser)

gnomAD frequency: 0.00054  dbSNP: rs111033363

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000039734	SCV000063423	likely benign	not specified	2018-11-20	criteria provided, single submitter	clinical testing	p.Arg1273Ser in PCDH15 is classified as likely benign because it has been identi fied in 0.08% (116/129078) of European chromosomes by gnomAD (http://gnomad.broa dinstitute.org) and it has been identified in two individuals with Usher syndrom e who had alternate causes of the Usher syndrome identified. One individual had two pathogenic variants in PCDH15 and the other individual had two pathogenic va riants in MYO7A (Bujakowska 2014, LMM unpublished data). This variant has also been identified in another 3 individuals with Usher syndrome and 2 individuals w ith hearing loss; however, a pathogenic variant affecting the remaining copy of PCDH15 was not identified in these individuals (Bonnet 2011, Jaijo 2012, LMM unp ublished data). ACMG/AMP criteria applied: BS1_Supporting, BP2.
Eurofins Ntd Llc (ga)	RCV000727028	SCV000705032	uncertain significance	not provided	2018-02-16	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763655	SCV000894535	uncertain significance	Autosomal recessive nonsyndromic hearing loss 23; Usher syndrome type 1D; Usher syndrome type 1F	2018-10-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000727028	SCV001147898	likely benign	not provided	2023-11-01	criteria provided, single submitter	clinical testing	PCDH15: BP4, BS1:Supporting, BS2
Illumina Laboratory Services, Illumina	RCV001104870	SCV001261765	uncertain significance	Usher syndrome type 1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000727028	SCV001420672	likely benign	not provided	2025-02-03	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001449585	SCV001652724	uncertain significance	Usher syndrome type 1F	2021-05-18	criteria provided, single submitter	clinical testing
Pars Genome Lab	RCV001449585	SCV001736820	uncertain significance	Usher syndrome type 1F	2021-05-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000727028	SCV001768395	uncertain significance	not provided	2022-03-11	criteria provided, single submitter	clinical testing	Identified as heterozygous in patients with Usher syndrome type I in published literature, with either no second variant identified (Jaijo et al., 2012) or no available information about other variants present in the same individual (Bonnet et al., 2011); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 21569298, 25468891, 22815625, 30245029, 34426522)
Myriad Genetics, Inc.	RCV001810408	SCV002060100	uncertain significance	Usher syndrome type 1D	2021-11-04	criteria provided, single submitter	clinical testing	NM_033056.3(PCDH15):c.3817C>A(R1273S) is a missense variant classified as a variant of uncertain significance in the context of PCDH15-related disorders. R1273S has been observed in cases with relevant disease (PMID: 25468891, 22815625, 21569298). Functional assessments of this variant are not available. R1273S has been observed in population frequency databases (gnomAD: NFE 0.09%). In summary, there is insufficient evidence to classify NM_033056.3(PCDH15):c.3817C>A(R1273S) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004814969	SCV005070012	uncertain significance	Retinal dystrophy	2022-01-01	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000727028	SCV005411005	uncertain significance	not provided	2023-05-11	criteria provided, single submitter	clinical testing	BS1_supporting