Submissions for variant NM_001384140.1(PCDH15):c.3358C>T (p.Arg1120Ter)

gnomAD frequency: 0.00001  dbSNP: rs773404494

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000223562	SCV000271434	pathogenic	Rare genetic deafness	2022-03-30	criteria provided, single submitter	clinical testing	The p.Arg1120X variant in PCDH15 has been reported in one individual with congenital hearing loss who also had a second pathogenic PCDH15 variant, and by our laboratory in another individual with congenital hearing loss who also had with a second pathogenic PCDH15 variant (Kletke 2017 PMID: 27743452, LMM data). It has also been identified in 0.03% (1/347) of Finnish chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this frequency is low enough to be consistent with a recessive allele frequency. This variant has also been reported in ClinVar (Variation ID 228389). This nonsense variant leads to a premature termination codon at position 1120, 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. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome. ACMG/AMP Criteria applied: PVS1, PM3_Strong.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000797689	SCV000937263	pathogenic	not provided	2024-08-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1120*) 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 0.004%). This premature translational stop signal has been observed in individual(s) with a PCDH15-related condition (PMID: 27743452). ClinVar contains an entry for this variant (Variation ID: 228389). For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001833187	SCV003761053	pathogenic	Usher syndrome type 1F	2023-01-24	criteria provided, single submitter	curation	The p.Arg1120Ter variant in PCDH15 has been reported in 1 individual, in the compound heterozygous state, with Usher syndrome type 1F (PMID: 27743452), and has been identified in 0.009% (1/10602) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs773404494). 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#: 228389) and has been interpreted as pathogenic by Laboratory for Molecular Medicine (Mass General Brigham Personalized Medicine), Invitae, and Natera, Inc.. This nonsense variant leads to a premature termination codon at position 1120, 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 (Richards 2015).
Baylor Genetics	RCV003474996	SCV004200769	pathogenic	Autosomal recessive nonsyndromic hearing loss 23	2024-02-06	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005044438	SCV005675235	pathogenic	Autosomal recessive nonsyndromic hearing loss 23; Usher syndrome type 1D; Usher syndrome type 1F	2024-04-23	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001833187	SCV002092946	pathogenic	Usher syndrome type 1F	2021-01-14	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004734863	SCV005357279	likely pathogenic	PCDH15-related disorder	2024-08-09	no assertion criteria provided	clinical testing	The PCDH15 c.3358C>T variant is predicted to result in premature protein termination (p.Arg1120*). This variant was reported as pathogenic in individuals with Usher syndrome and inherited retinal disorders (Kletke et al. 2017. PubMed ID: 27743452; Table S1, Karali et al. 2022. PubMed ID: 36460718). This variant is reported in 0.029% of alleles in individuals of European (Finnish) descent in gnomAD. Nonsense variants in PCDH15 are expected to be pathogenic. This variant is interpreted as likely pathogenic.