Submissions for variant NM_022124.6(CDH23):c.1515-12G>A

gnomAD frequency: 0.00002  dbSNP: rs369396703

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV001089674	SCV001245157	uncertain significance	Usher syndrome	2023-10-18	reviewed by expert panel	curation	The c.1515-12G>A variant in CDH23 is an intronic variant which is located in intron 15. The highest population minor allele frequency in gnomAD v2.1.1 is 0.009% ( 2/21986) in the African/African American population (PM2_supporting, BS1, and BA1 not met). The results from 3 in silico splicing predictors including MaxEntScan indicate that this variant may affect splicing by disrupting the acceptor splice site (PP3). This variant has been detected in 3 individuals with hearing loss and 2 individuals with Usher syndrome. The individuals with Usher syndrome were compound heterozygous for the variant and a pathogenic or likely pathogenic variant; however, phase was not confirmed in trans (PM3, PP4, SCV000564845.4, SCV000804605.2). In summary, this variant is classified as uncertain significance based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PP3, PM3, PP4 (ClinGen Hearing Loss VCEP specifications version 2; 10.18.2023).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000216452	SCV000271550	uncertain significance	not specified	2015-08-11	criteria provided, single submitter	clinical testing	The c.1515-12G>A variant in CDH23 has not been previously reported in individual s with hearing loss or Usher syndrome, but has been identified in 1/26694 Europe an chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinsti tute.org; rs369396703). Although this variant has been seen in the general popu lation, its frequency is not high enough to rule out a pathogenic role. This var iant is located in the 3' splice region. Computational tools suggest an impact to splicing. However, this information is not predictive enough to determine pat hogenicity. In summary, the clinical significance of the c.1515-12G>A variant is uncertain.
GeneDx	RCV000486086	SCV000564845	uncertain significance	not provided	2024-05-02	criteria provided, single submitter	clinical testing	Identified with a second CDH23 variant in patients with bilateral sensorineural hearing loss referred for genetic testing at GeneDx and in published literature (PMID: 32467589); Classified as a variant of uncertain significance by the ClinGen Hearing Loss Expert Panel (ClinVar SCV001245157.1; Oza et al., 2018); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 32467589, 37575969, 34997062)
INGEBI, INGEBI / CONICET	RCV001544540	SCV001763586	likely pathogenic	Nonsyndromic genetic hearing loss	2021-07-15	criteria provided, single submitter	clinical testing	Already curated by HL expert panel. The allele frequency of the c.1515-12G>A variant in the CDH23 gene is 0.01% (1/9692) of Ashkenazi Jewish chromosomes by gnomAD, which is a low enough frequency to apply PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_Supporting). Computational prediction tools and conservation analysis suggest that the c.1515-12G>A variant may impact splicing (PP3). This variant was reported in two patients with Usher syndrome (GeneDx unpublished data SCV000564845.2, Human Genetics Radboudumc unpublished data SCV000804605.2) and one with sloping sensorineural hearing loss (LMM unpublished data SCV000271550.2). The probands with Usher syndrome had a suspected-pathogenic variant in CDH23 with an unknown phase (PM3; SCV000564845.2, SCV000804605.2). In this study, two siblings with non-sydromic hearing loss (high frequencies affected )carried this variant in trans with A366T applying to PP1_Sup. In summary, the clinical significance of this variant is Likely Pathogenic based on the ACMG/AMP and gene-specific hearing loss Expert panel standars and guidelines (PM2_Supporting, PM3, PP3, PP1_Sup)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000486086	SCV002224633	uncertain significance	not provided	2022-07-26	criteria provided, single submitter	clinical testing	This sequence change falls in intron 15 of the CDH23 gene. It does not directly change the encoded amino acid sequence of the CDH23 protein. This variant is present in population databases (rs369396703, gnomAD 0.01%). This variant has been observed in individual(s) with autosomal recessive deafness (PMID: 32467589). ClinVar contains an entry for this variant (Variation ID: 228484). 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 available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Baylor Genetics	RCV003474998	SCV004210576	likely pathogenic	Pituitary adenoma 5, multiple types	2023-10-30	criteria provided, single submitter	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000678531	SCV000804605	uncertain significance	Usher syndrome type 1D	2016-09-01	no assertion criteria provided	clinical testing
Natera, Inc.	RCV001833194	SCV002091219	uncertain significance	Usher syndrome type 1	2020-08-10	no assertion criteria provided	clinical testing