Submissions for variant NM_001384140.1(PCDH15):c.1209T>G (p.Tyr403Ter)

dbSNP: rs759187261

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000795013	SCV000934451	pathogenic	not provided	2018-11-20	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in PCDH15 are known to be pathogenic (PMID: 11398101, 11487575, 14570705). This variant has not been reported in the literature in individuals with PCDH15-related disease. This variant is present in population databases (rs759187261, ExAC 0.001%). This sequence change creates a premature translational stop signal (p.Tyr403*) in the PCDH15 gene. It is expected to result in an absent or disrupted protein product.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002536992	SCV003761083	likely pathogenic	Usher syndrome type 1F	2023-01-24	criteria provided, single submitter	curation	The p.Tyr403Ter variant in PCDH15 has not been reported in the literature in individuals with Usher syndrome type 1F and has been identified in 0.0009% (1/113740) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs759187261). 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#: 641711) and has been interpreted as pathogenic by Invitae. This nonsense variant leads to a premature termination codon at position 403, 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, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive Usher syndrome type 1F. ACMG/AMP Criteria applied: PVS1, PM2 (Richards 2015).
Fulgent Genetics, Fulgent Genetics	RCV005047063	SCV005677161	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 23; Usher syndrome type 1D; Usher syndrome type 1F	2024-06-13	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004735805	SCV005362170	likely pathogenic	PCDH15-related disorder	2024-08-05	no assertion criteria provided	clinical testing	The PCDH15 c.1209T>G variant is predicted to result in premature protein termination (p.Tyr403*). To our knowledge, this variant has not been previously reported in the literature. This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in PCDH15 are expected to be pathogenic. This variant is interpreted as likely pathogenic.