Submissions for variant NM_001384140.1(PCDH15):c.3717+2dup

gnomAD frequency: 0.00001  dbSNP: rs1248401224

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000669022	SCV000793718	uncertain significance	Usher syndrome type 1F	2017-08-29	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000808578	SCV000948690	pathogenic	not provided	2023-08-10	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 27, but is expected to preserve the integrity of the reading-frame (PMID: 23451239). ClinVar contains an entry for this variant (Variation ID: 553548). This variant is also known as c.3717+2dupTT. This variant has been observed in individual(s) with Usher syndrome (PMID: 22815625, 25404053). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (no rsID available, gnomAD 0.009%). This sequence change falls in intron 27 of the PCDH15 gene. It does not directly change the encoded amino acid sequence of the PCDH15 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product.
GeneDx	RCV000808578	SCV002818943	likely pathogenic	not provided	2023-01-05	criteria provided, single submitter	clinical testing	Published functional studies suggest the c.3717+2dupT results in the skipping of exon 27 and utilization of a cryptic splice site (Aparisi et al., 2013); Intronic splice site variant in a gene for which loss of function is a known mechanism of disease, and both splice predictors and evolutionary conservation support a deleterious effect.; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25404053, 22815625, 23451239)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000669022	SCV002819726	likely pathogenic	Usher syndrome type 1F	2022-12-21	criteria provided, single submitter	clinical testing	Variant summary: PCDH15 c.3717+2dupT alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing, significantly altering the expected protein size. (Aparisi_2013). The variant allele was found at a frequency of 1.2e-05 in 250884 control chromosomes. c.3717+2dupT has been reported in the literature in individuals affected with Usher Syndrome Type 1F (e.g. Jaijo_2012, Aparisi_2014). These data indicate that the variant is likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, with one lab citing the variant as pathogenic, one as likely pathogenic, and one as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000669022	SCV003761048	likely pathogenic	Usher syndrome type 1F	2023-01-24	criteria provided, single submitter	curation	The c.3717+2dup variant in PCDH15 has been reported in 2 individuals with Usher syndrome type 1F (PMID: 22815625, 23451239, 25404053) and has been identified in 0.009% (3/34464) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1248401224). 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#: 553548) and has been interpreted as pathogenic or likely pathogenic by Invitae and Natera, Inc., and as a variant of uncertain significance by Counsyl. Of the 2 affected individuals, 1 of those was a homozygote and 1 was a compound heterozygote that carried a reported pathogenic variant with unknown phase, which increases the likelihood that the c.3717+2dup variant is pathogenic (PMID: 22815625, 23451239, 25404053). In vitro functional studies provide some evidence that the c.3717+2dup variant may impact protein function (PMID: 23451239). However, these types of assays may not accurately represent biological function. This variant is located in the 3’ splice region. Computational tools do suggest an impact to splicing. However, this information is not predictive enough to determine pathogenicity. 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: PM2_supporting, PP3, PM3, PS3_moderate (Richards 2015).
Baylor Genetics	RCV004568520	SCV005055125	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 23	2023-11-29	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000669022	SCV002094851	likely pathogenic	Usher syndrome type 1F	2020-10-30	no assertion criteria provided	clinical testing