Submissions for variant NM_001384140.1(PCDH15):c.3316C>T (p.Arg1106Ter)

gnomAD frequency: 0.00002  dbSNP: rs202033121

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000824731	SCV000063412	pathogenic	Rare genetic deafness	2017-08-15	criteria provided, single submitter	clinical testing	The p.Arg1106X variant in PCDH15 has been reported in the homozygous state in on e individual with Usher syndrome type I (Ammar-Khodja 2009). It has also been id entified in 5/111450 European chromosomes by the Genome Aggregation Database (gn omAD, http://gnomad.broadinstitute.org; dbSNP rs202033121). Although this varian t has been seen in the general population, its frequency is low enough to be con sistent with a recessive carrier frequency. The p.Arg1106X variant leads to a pr emature stop codon at position 1106, which is predicted to lead to a truncated o r absent protein. In summary, this variant meets criteria to be classified as pa thogenic for autosomal recessive Usher syndrome based on the previously reported individual, low frequency in the general population, and predicted loss of func tion of the protein.
Counsyl	RCV000039723	SCV000220613	likely pathogenic	Usher syndrome type 1F	2014-08-20	criteria provided, single submitter	literature only
Fulgent Genetics, Fulgent Genetics	RCV000515240	SCV000611293	pathogenic	Autosomal recessive nonsyndromic hearing loss 23; Usher syndrome type 1D; Usher syndrome type 1F	2017-05-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001386496	SCV001586740	pathogenic	not provided	2024-10-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1106*) 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 (rs202033121, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with Usher syndrome (PMID: 18484607, 19375528). ClinVar contains an entry for this variant (Variation ID: 46464). For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000039723	SCV003761054	pathogenic	Usher syndrome type 1F	2023-01-24	criteria provided, single submitter	curation	The p.Arg1106Ter variant in PCDH15 has been reported in 2 individuals with Usher syndrome type 1F (PMID: 19375528, 18484607) and has been identified in 0.004% (5/113538) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs202033121). 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#: 46464) and has been interpreted as pathogenic or likely pathogenic by Fulgent Genetics, Counsyl, Laboratory for Molecular Medicine (Mass General Brigham Personalized Medicine), Invitae, and Natera, Inc.. Of the 2 affected individuals, 1 of those was a homozygote, which increases the likelihood that the p.Arg1106Ter variant is pathogenic (PMID: 19375528). This nonsense variant leads to a premature termination codon at position 1106, 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, PM2_supporting, PM3_supporting (Richards 2015).
Revvity Omics, Revvity	RCV001386496	SCV003808722	likely pathogenic	not provided	2022-03-30	criteria provided, single submitter	clinical testing
SN ONGC Dept of Genetics and Molecular biology Vision Research Foundation	RCV003389450	SCV003927118	pathogenic	Usher syndrome	2022-12-31	criteria provided, single submitter	research
Baylor Genetics	RCV003473289	SCV004200771	pathogenic	Autosomal recessive nonsyndromic hearing loss 23	2023-11-22	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000039723	SCV002092957	pathogenic	Usher syndrome type 1F	2021-10-15	no assertion criteria provided	clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV003473289	SCV004801128	pathogenic	Autosomal recessive nonsyndromic hearing loss 23	2024-02-11	flagged submission	research