Submissions for variant NM_001384140.1(PCDH15):c.1927C>T (p.Arg643Ter)

dbSNP: rs727504301

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000824734	SCV000203994	pathogenic	Rare genetic deafness	2014-02-10	criteria provided, single submitter	clinical testing	The Arg643X variant in PCDH15 has been reported in two individuals with Usher sy ndrome (Ahmed 2003, Roux 2006), and was not identified in large population studi es. Both of these individuals were homozygous or compound heterozygous with a se cond pathogenic variant and this variant segregated in two affected siblings. Th is nonsense variant leads to a premature termination codon at position 643, whic h is predicted to lead to a truncated or absent protein. In summary, this varian t meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/L MM).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000154331	SCV000917971	pathogenic	Usher syndrome type 1F	2018-09-07	criteria provided, single submitter	clinical testing	Variant summary: PCDH15 c.1927C>T (p.Arg643X) 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. A truncation downstream of this position have been classified as pathogenic by our laboratory (c.2971C>T (p.Arg991X)). The variant was absent in 246434 control chromosomes (gnomAD and publication data). c.1927C>T has been reported in the literature as a homozygous and compound heterozygous allele in multiple individuals affected with Usher Syndrome Type 1F (Ahmed 2003, Roux 2006). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals	RCV001002687	SCV001156366	pathogenic	Usher syndrome type 1D	2019-02-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001386498	SCV001586742	pathogenic	not provided	2024-11-05	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg643*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Usher syndrome (PMID: 14570705). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 177724). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002498738	SCV002810130	pathogenic	Autosomal recessive nonsyndromic hearing loss 23; Usher syndrome type 1D; Usher syndrome type 1F	2022-04-27	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV004567176	SCV005055109	pathogenic	Autosomal recessive nonsyndromic hearing loss 23	2024-03-18	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000154331	SCV002088566	pathogenic	Usher syndrome type 1F	2021-03-31	no assertion criteria provided	clinical testing