Submissions for variant NM_001384140.1(PCDH15):c.2785C>T (p.Arg929Ter)

gnomAD frequency: 0.00001  dbSNP: rs1057516342

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000412338	SCV000485499	likely pathogenic	Usher syndrome type 1F	2015-12-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000811416	SCV000951682	pathogenic	not provided	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg929*) 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 (no rsID available, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with Usher syndrome (PMID: 15660226, 25307757, 25425308). ClinVar contains an entry for this variant (Variation ID: 370242). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000412338	SCV001361472	pathogenic	Usher syndrome type 1F	2022-11-16	criteria provided, single submitter	clinical testing	Variant summary: PCDH15 c.2785C>T (p.Arg929X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 250804 control chromosomes. c.2785C>T has been reported in the literature in individuals affected with Usher Syndrome Type 1F (Ouyang_2005, Zein_2014, Sethna_2021), and was also identified in a carrier screening study (Perreault-Micale_2014). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000412338	SCV003761061	pathogenic	Usher syndrome type 1F	2023-01-24	criteria provided, single submitter	curation	The p.Arg929Ter variant in PCDH15 has been reported in 4 individuals with Usher syndrome type 1F (PMID: 15660226, 25307757, 25425308) and has been identified in 0.003% (1/34576) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1057516342). 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#: 370242) and has been interpreted as pathogenic or likely pathogenic by Counsyl, Invitae, Women's Health and Genetics/Laboratory Corporation of America (LabCorp), and Genetic Testing Center for Deafness (Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital). Of the 4 affected individuals, 2 were a compound heterozygotes that carried a reported pathogenic variant with unknown phase, which increases the likelihood that the p.Arg929Ter variant is pathogenic (VariationID: 4933; PMID: 25425308). This nonsense variant leads to a premature termination codon at position 929, 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 (Richards 2015).
Baylor Genetics	RCV000770852	SCV004200839	pathogenic	Autosomal recessive nonsyndromic hearing loss 23	2023-11-10	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005049535	SCV005681965	pathogenic	Autosomal recessive nonsyndromic hearing loss 23; Usher syndrome type 1D; Usher syndrome type 1F	2024-06-21	criteria provided, single submitter	clinical testing
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital	RCV000770852	SCV000902354	pathogenic	Autosomal recessive nonsyndromic hearing loss 23	2019-02-26	no assertion criteria provided	case-control