Submissions for variant NM_022124.6(CDH23):c.9904G>A (p.Glu3302Lys)

gnomAD frequency: 0.00006  dbSNP: rs368743687

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000218211	SCV000271579	uncertain significance	not specified	2015-01-26	criteria provided, single submitter	clinical testing	The p.Glu3302Lys variant in CDH23 has been previously reported in 1 individual w ith Usher syndrome type I; however a second variant in CDH23 was not identified in that individual (Besnard 2014). It has also been identified in 2/57864 Europe an chromosomes and 4/22950 Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs368743687). Although this varian t has been seen in the general population, its frequency is not high enough to r ule out a pathogenic role. Computational prediction tools and conservation analy sis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical sign ificance of the p.Glu3302Lys variant is uncertain.
Invitae	RCV001041568	SCV001205192	uncertain significance	not provided	2022-07-23	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 3302 of the CDH23 protein (p.Glu3302Lys). This variant is present in population databases (rs368743687, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with CDH23-related conditions. ClinVar contains an entry for this variant (Variation ID: 228512). 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.
Baylor Genetics	RCV001332452	SCV001524780	uncertain significance	Autosomal recessive nonsyndromic hearing loss 12	2019-08-21	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000218211	SCV002041768	uncertain significance	not specified	2021-11-18	criteria provided, single submitter	clinical testing	Variant summary: CDH23 c.9904G>A (p.Glu3302Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5e-05 in 241642 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in CDH23 causing Usher Syndrome (5e-05 vs 0.0032), allowing no conclusion about variant significance. c.9904G>A has been reported in the literature in a heterozygous individual affected with Usher Syndrome (Besnard_2014). This report does not provide unequivocal conclusions about association of the variant with Usher Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV002500708	SCV002789784	uncertain significance	Autosomal recessive nonsyndromic hearing loss 12; Usher syndrome type 1D; Pituitary adenoma 5, multiple types	2022-04-21	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001828070	SCV002086397	uncertain significance	Usher syndrome type 1	2020-03-22	no assertion criteria provided	clinical testing