Submissions for variant NM_001384140.1(PCDH15):c.1737C>G (p.Tyr579Ter)

dbSNP: rs1057517251

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000410287	SCV000486983	likely pathogenic	Usher syndrome type 1F	2016-09-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000410287	SCV000917969	likely pathogenic	Usher syndrome type 1F	2018-06-11	criteria provided, single submitter	clinical testing	Variant summary: PCDH15 c.1737C>G (p.Tyr579X) 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 (e.g., p.Arg991X). The variant allele was found at a frequency of 4.1e-06 in 245806 control chromosomes, which does not exceed the maximal expected allele frequency for a pathogenic variant in PCDH15. c.1737C>G has been reported in the literature in individuals affected with Usher Syndrome Type 1F (Jaijo_2012, Kletke_2017). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001050534	SCV001214649	pathogenic	not provided	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr579*) 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: 22815625, 27743452, 30459346). This variant is also known as Tyr584X. ClinVar contains an entry for this variant (Variation ID: 371411). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001073718	SCV001239277	pathogenic	Retinal dystrophy	2017-07-26	criteria provided, single submitter	clinical testing
National Institute on Deafness and Communication Disorders, National Institutes of Health	RCV001328031	SCV001519364	pathogenic	Childhood onset hearing loss	2021-07-08	criteria provided, single submitter	research	PVS1, PS1, PM1, PM2, PP1_moderate (1.33) / Modifications from PMID: 30311386 for classification: The genetic causes of hearing loss have not yet been well characterized in the Yoruba population, and the information regarding variant MAF in this population is still limited, so we did not exclude any variant based on their "high" MAF. PP3 criteria was applied even if the REVEL score was below 0.7, if at least two of the pathogenicity prediction algorithms used predicted that the variant was damaging or likely damaging.
GeneDx	RCV001050534	SCV002540296	pathogenic	not provided	2022-06-24	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23451239, 27743452, 30390570, 31589614, 30459346, 22815625)
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000410287	SCV003761074	pathogenic	Usher syndrome type 1F	2023-01-24	criteria provided, single submitter	curation	The p.Tyr579Ter variant in PCDH15 has been reported in 4 individuals with Usher syndrome type 1F (PMID: 27743452, 30390570, 30459346, 22815625) and has been identified in 0.003% (1/34534) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1057517251). 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#: 371411) and has been interpreted as pathogenic or likely pathogenic by Counsyl, Invitae, Women's Health and Genetics/Laboratory Corporation of America (LabCorp), Blueprint Genetics, and National Institute on Deafness and Communication Disorders (National Institutes of Health). Of the 4 affected individuals, 2 of those were homozygotes, which increases the likelihood that the p.Tyr579Ter variant is pathogenic (PMID: 30390570, 30459346). This nonsense variant leads to a premature termination codon at position 579, 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).
PreventionGenetics, part of Exact Sciences	RCV004530499	SCV004105034	pathogenic	PCDH15-related disorder	2023-04-19	criteria provided, single submitter	clinical testing	The PCDH15 c.1737C>G variant is predicted to result in premature protein termination (p.Tyr579*). This variant has been reported as pathogenic for Usher syndrome (also described as c.1752C>G p.Tyr584Ter; Jaijo. 2012. PubMed ID: 22815625; Kletke. et al 2017. PubMed ID: 27743452; Soares de Lima. et al 2018. PubMed ID: 30390570; Table S3, Batissoco. et al 2021. PubMed ID: 34599368). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-55912907-G-C). Nonsense variants in PCDH15 are expected to be pathogenic. This variant is interpreted as pathogenic.
Baylor Genetics	RCV003475969	SCV004200778	pathogenic	Autosomal recessive nonsyndromic hearing loss 23	2024-03-12	criteria provided, single submitter	clinical testing