Submissions for variant NM_001384140.1(PCDH15):c.3717+1G>T

dbSNP: rs748706627

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001386495	SCV001586739	pathogenic	not provided	2023-06-23	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 27 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 (rs748706627, gnomAD 0.002%). Disruption of this splice site has been observed in individual(s) with hearing impairment (PMID: 18719945). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1073476). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV001810507	SCV002060142	likely pathogenic	Usher syndrome type 1D	2021-11-16	criteria provided, single submitter	clinical testing	NM_033056.3(PCDH15):c.3717+1G>T is a canonical splice variant classified as likely pathogenic in the context of PCDH15-related disorders. c.3717+1G>T has been observed in cases with relevant disease (PMID: 18719945). Functional assessments of this variant are not available in the literature. c.3717+1G>T has been observed in population frequency databases (gnomAD: NFE 0.002%). In summary, NM_033056.3(PCDH15):c.3717+1G>T is a canonical splice variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002551549	SCV003761049	pathogenic	Usher syndrome type 1F	2023-01-24	criteria provided, single submitter	curation	The c.3717+1G>T variant in PCDH15 has been reported in 1 individual, in the homozygous state, with Usher syndrome type 1F (PMID: 18719945), segregated with disease in 5 affected relatives from 1 family (PMID: 18719945), and has been identified in 0.002% (2/128820) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs748706627). 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#: 1073476) and has been interpreted as pathogenic or likely pathogenic by Invitae and Myriad Women's Health, Inc.. This variant is located in the 3' splice region. Computational tools predict use of a cryptic splice site that includes translation of a premature termination codon, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome type 1F. ACMG/AMP Criteria applied: PP1_strong, PVS1, PM2_supporting, PM3_supporting (Richards 2015).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002551549	SCV003928635	pathogenic	Usher syndrome type 1F	2023-04-06	criteria provided, single submitter	clinical testing	Variant summary: PCDH15 c.3717+1G>T is located in 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 the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 250906 control chromosomes (gnomAD). c.3717+1G>T has been reported in the literature in multiple individuals affected with Usher Syndrome Type 1F and the variant segregated with the disease (example: Ahmed_2018). 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. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV003473966	SCV004200795	pathogenic	Autosomal recessive nonsyndromic hearing loss 23	2023-08-18	flagged submission	clinical testing