Submissions for variant NM_001384140.1(PCDH15):c.1440+2T>C

dbSNP: rs1363688830

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001377586	SCV001574956	likely pathogenic	not provided	2021-11-30	criteria provided, single submitter	clinical testing	This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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: 1066564). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This sequence change affects a donor splice site in intron 12 of the PCDH15 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PCDH15 are known to be pathogenic (PMID: 11398101, 11487575, 14570705).
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002550243	SCV003761081	likely pathogenic	Usher syndrome type 1F	2023-01-24	criteria provided, single submitter	curation	The c.1440+2T>C variant in PCDH15 has not been previously reported in the literature in individuals with Usher syndrome type 1F but has been identified in 0.0009% (1/113550) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1363688830). 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#: 1066564) and has been interpreted as likely pathogenic by Invitae. This variant is located in the 3' splice region. Computational tools predict a splicing impact through use of an out of frame cryptic splice site, though 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, PVS1 (Richards 2015).