Submissions for variant NM_022124.6(CDH23):c.901C>T (p.Arg301Trp)

gnomAD frequency: 0.00001  dbSNP: rs397517364

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000039302	SCV000062986	uncertain significance	not specified	2011-04-26	criteria provided, single submitter	clinical testing	The Arg301Trp variant in CDH23 has not been reported in the literature nor previ ously identified by our laboratory. However, another amino acid change (Arg301Gl n) occurs at this position, which has been reported in two Japanese probands wit h hearing loss, both carrying the variant with a second CDH23 variant (Wagatsuma 2007). Furthermore, this residue is highly conserved across species and computa tional analyses (PolyPhen2, SIFT, AlignGVGD) suggest that the Arg301Trp variant may impact the protein. However, this information is not predictive enough to as sume pathogenicity. In summary, the clinical significance of this variant cannot be determined with certainty at this time; however based upon the arguments des cribed above, we would lean towards a more likely pathogenic role.
Eurofins Ntd Llc (ga)	RCV000727113	SCV000705834	uncertain significance	not provided	2017-02-06	criteria provided, single submitter	clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV001374887	SCV001572169	uncertain significance	Usher syndrome type 1D	2021-04-08	criteria provided, single submitter	research	The CDH23 c.901C>T variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PP3. Based on this evidence we have classified this variant as Variant of Uncertain Significance.
Invitae	RCV000727113	SCV002187346	uncertain significance	not provided	2022-06-12	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 301 of the CDH23 protein (p.Arg301Trp). This variant is present in population databases (rs397517364, gnomAD 0.004%). 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: 46066). 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 C65"). This variant disrupts the p.Arg301 amino acid residue in CDH23. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17850630). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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	RCV000039302	SCV004029644	uncertain significance	not specified	2023-07-26	criteria provided, single submitter	clinical testing	Variant summary: CDH23 c.901C>T (p.Arg301Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five 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 249228 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.901C>T has been reported in the literature in at least one individual affected with sensorineural hearing loss along with a pathogenic variant (Usami_2022). These data do not allow any conclusion about variant significance. A different affecting the same codon (p.Arg301Gln) has been classified as pathogenic by the ClinGen Hearing Loss Variant Curation Expert Panel, suggesting the codon is important for protein function. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 35020051). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Natera, Inc.	RCV001275418	SCV001460568	uncertain significance	Usher syndrome type 1	2020-01-24	no assertion criteria provided	clinical testing