Submissions for variant NM_022124.6(CDH23):c.9094G>A (p.Asp3032Asn)

gnomAD frequency: 0.00001  dbSNP: rs368603948

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000155057	SCV000204741	uncertain significance	not specified	2014-07-24	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The Asp3032Asn variant in CDH23 has not been previously reported in individuals with hearing lo ss, but has been identified in 1/8432 of European American chromosomes by the NH LBI Exome Sequencing Project (http://evs.gs.washington.edu). Although this varia nt has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation anal yses suggest that the Asp3032Asn variant may impact the protein, though this inf ormation is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain.
Blueprint Genetics	RCV001075188	SCV001240801	uncertain significance	Retinal dystrophy	2018-11-06	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001850121	SCV002202825	uncertain significance	not provided	2021-12-21	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 3032 of the CDH23 protein (p.Asp3032Asn). This variant is present in population databases (rs368603948, gnomAD 0.002%). This missense change has been observed in individual(s) with hearing loss (PMID: 26969326). ClinVar contains an entry for this variant (Variation ID: 178313). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000155057	SCV002819670	uncertain significance	not specified	2022-12-02	criteria provided, single submitter	clinical testing	Variant summary: CDH23 c.9094G>A (p.Asp3032Asn) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 249054 control chromosomes (gnomAD). c.9094G>A has been reported in the literature as a biallelic genotype in individuals affected with non-syndromic hearing loss (e.g. Sloan-Heggen_2016, Usami_2022). These data indicate that the variant may 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 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV001850121	SCV005436655	uncertain significance	not provided	2024-09-01	criteria provided, single submitter	clinical testing	CDH23: PM2:Supporting
Natera, Inc.	RCV001826833	SCV002092110	uncertain significance	Usher syndrome type 1	2020-11-24	no assertion criteria provided	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV001075188	SCV005072288	likely pathogenic	Retinal dystrophy	2018-01-01	no assertion criteria provided	clinical testing