Submissions for variant NM_022124.6(CDH23):c.3178C>T (p.Arg1060Trp)

gnomAD frequency: 0.00035  dbSNP: rs201536811

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000217321	SCV000271556	uncertain significance	not specified	2015-05-17	criteria provided, single submitter	clinical testing	The p.Arg1060Trp variant in CDH23 has been previously reported in 6 probands wit h Usher syndrome, one individual with possible Usher syndrome, and one individua l with sensorineural hearing loss (Astuto 2002, Roux 2006, Cremers 2007, Jaijo 2 010, Bonnet 2011, Kimberling 2010, Vozzi 2011, Bujakowska 2014). However, most o f these individuals did not carry a second variant in CDH23 and two of the Usher individuals had pathogenic variants identified in other Usher syndrome genes th at explain their clinical manifestations (Vozzi 2011, Bonnet 2011). This variant has been identified in 0.06% (40/66008) of European chromosomes by the Exome Ag gregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs201536811); however, this frequency is not high enough to rule out a pathogenic role. Comput ational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determi ne pathogenicity. In summary, the clinical significance of the p.Arg1060Trp vari ant is uncertain.
Eurofins Ntd Llc (ga)	RCV000726009	SCV000341197	uncertain significance	not provided	2018-06-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000726009	SCV000568155	uncertain significance	not provided	2016-05-19	criteria provided, single submitter	clinical testing	The R1060W variant in the CDH23 gene has been reported previously in association with Usher syndrome and hearing loss (Roux et al., 2006; Jaijo et al., 2010; Bonnet et al., 2011; Bujakowska et al., 2014). However, in these reports the variant was either observed with no other CDH23 variants or with other variants which were determined to be the cause of the patient's phenotype, and was often described as non-pathogenic. Additionally, the variant has been observed in cis with D1341N (Cremers et al., 2007). However, the variant was not observed at any significant frequency in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000217321	SCV001158879	uncertain significance	not specified	2019-04-18	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001106599	SCV001263675	uncertain significance	Autosomal recessive nonsyndromic hearing loss 12	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000726009	SCV001414994	uncertain significance	not provided	2022-10-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1060 of the CDH23 protein (p.Arg1060Trp). This variant is present in population databases (rs201536811, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Usher syndrome or hearing loss (PMID: 16679490, 21569298, 25468891). ClinVar contains an entry for this variant (Variation ID: 226437). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CDH23 protein function. 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.
CeGaT Center for Human Genetics Tuebingen	RCV000726009	SCV005093142	uncertain significance	not provided	2024-07-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000217321	SCV005380826	uncertain significance	not specified	2024-08-08	criteria provided, single submitter	clinical testing	Variant summary: CDH23 c.3178C>T (p.Arg1060Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00048 in 248684 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in CDH23 causing Usher Syndrome (0.00048 vs 0.0032), allowing no conclusion about variant significance. c.3178C>T has been reported in the literature in individuals affected with Usher Syndrome or nonsyndromic hearing loss. These reports do 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. The following publications have been ascertained in the context of this evaluation (PMID: 12075507, 25468891, 35580552). ClinVar contains an entry for this variant (Variation ID: 226437). Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneReviews	RCV000221834	SCV000268753	not provided	Usher syndrome type 1		no assertion provided	literature only
Natera, Inc.	RCV000221834	SCV001453334	uncertain significance	Usher syndrome type 1	2020-09-16	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000726009	SCV001957464	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000726009	SCV001973910	uncertain significance	not provided		no assertion criteria provided	clinical testing