Submissions for variant NM_033056.4(PCDH15):c.4681_4684dup (p.Ser1562Ter)

dbSNP: rs730880357

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000156189	SCV000205905	uncertain significance	not specified	2013-11-19	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The 4681_4684du pAAGT (Ser1562X) variant in PCDH15 has not been previously reported in individua ls with hearing loss, but has been identified in 0.02% (2/4262) of African Ameri can chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington. edu/EVS/). This variant leads to a premature termination codon at position 1562; however, the termination codon occurs within the last coding exon of the gene. Therefore, nonsense mediated decay is not expected to occur and the impact to pr otein function is unknown. In summary, the clinical significance of this variant cannot be determined with certainty; however, based upon the predicted loss of 394 amino acids in the last exon of PCDH15, we would lean towards a more likely pathogenic role.
Invitae	RCV001224404	SCV001396596	pathogenic	not provided	2024-01-12	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser1562*) in the PCDH15 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 394 amino acid(s) of the PCDH15 protein. This variant is present in population databases (rs730880357, gnomAD 0.09%). This variant has not been reported in the literature in individuals affected with PCDH15-related conditions. ClinVar contains an entry for this variant (Variation ID: 179400). This variant disrupts a region of the PCDH15 protein in which other variant(s) (p.Gln1576*) have been determined to be pathogenic (PMID: 28281779). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001224404	SCV001772197	uncertain significance	not provided	2022-08-12	criteria provided, single submitter	clinical testing	Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 394 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Has not been previously published as pathogenic or benign with PCDH15-related condition to our knowledge; This variant is associated with the following publications: (PMID: 25307757, 15537665)
Baylor Genetics	RCV003474813	SCV004200882	uncertain significance	Autosomal recessive nonsyndromic hearing loss 23	2021-12-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000156189	SCV004241003	uncertain significance	not specified	2023-12-12	criteria provided, single submitter	clinical testing	Variant summary: PCDH15 c.4681_4684dupAAGT (p.Ser1562X) located in the last exon 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 7.6e-05 in 251038 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PCDH15 causing Usher Syndrome Type 1F (7.6e-05 vs 0.0032), allowing no conclusion about variant significance. Athough observed in cohorts of individuals undergoing carrier screening (example, Perreault-Micale_2014) and nonsyndromic hearing loss (example, Quaio_2022), to our knowledge, no penetrant association of c.4681_4684dupAAGT in individuals affected with Usher Syndrome Type 1F and no experimental evidence demonstrating its impact on protein function have been reported. Furthermore, the Clingen Hearing Loss Working Group expert panel has reported a limited association of PCDH15 gene with non-syndromic hearing loss (06/19/2018) and truncating variants in the majority of the cytoplasmic domain of this gene have been reported as unlikely to cause Usher Syndrome 1F (Perreault-Micale_2014). The following publications have been ascertained in the context of this evaluation (PMID: 25307757, 36147510). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV001274784	SCV001459209	uncertain significance	Usher syndrome type 1F	2020-09-16	no assertion criteria provided	clinical testing