Submissions for variant NM_001384140.1(PCDH15):c.706-3_717del

dbSNP: rs769348776

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000593242	SCV000708388	pathogenic	not provided	2017-05-17	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000593242	SCV000948187	pathogenic	not provided	2024-01-28	criteria provided, single submitter	clinical testing	This variant results in the deletion of part of exon 8 (c.706-3_717del) 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). This variant is present in population databases (rs769348776, gnomAD 0.007%). This variant has been observed in individual(s) with Usher syndrome (PMID: 28559085; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.706-5_715delAACAGGACCGTGCCC. ClinVar contains an entry for this variant (Variation ID: 501870). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002232235	SCV002511909	likely pathogenic	Usher syndrome type 1F	2022-04-07	criteria provided, single submitter	clinical testing	Variant summary: PCDH15 c.706-3_717del15 is spanning a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.6e-05 in 251040 control chromosomes (gnomAD). The variant, c.706-3_717del15, has been reported in the literature in at least one individual affected with retinal disease, which is was indicated to be consistent with the Usher Syndrome Type 1F phenotype (Stone_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002232235	SCV003761088	likely pathogenic	Usher syndrome type 1F	2023-01-24	criteria provided, single submitter	curation	The c.706-3_717del variant in PCDH15 has been reported in 2 individuals with Usher syndrome type 1F (internal data, PMID: 28559085), and has been identified in 0.006% (1/16256) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs769348776). 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#: 501870) and has been interpreted as pathogenic or likely pathogenic by Invitae, Women's Health and Genetics/Laboratory Corporation of America (LabCorp), and Eurofins NTD LLC (GA). Of the 2 affected individuals, 1 was a compound heterozygote that carried a reported pathogenic variant with unknown phase, which increases the likelihood that the c.706-3_717del variant is pathogenic (VariationID: 4933; internal data). This variant is located in the 5' splice region. Computational tools predict a splicing impact through the 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: PVS1_strong, PM2_supporting, PM3_supporting (Richards 2015).
Fulgent Genetics, Fulgent Genetics	RCV005044893	SCV005677201	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 23; Usher syndrome type 1D; Usher syndrome type 1F	2024-04-26	criteria provided, single submitter	clinical testing