Submissions for variant NM_022124.6(CDH23):c.6866A>G (p.Asn2289Ser)

dbSNP: rs876657756

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV001089673	SCV001245155	uncertain significance	Nonsyndromic genetic hearing loss	2022-12-21	reviewed by expert panel	curation	The NM_022124.6:c.6866A>G variant in the CDH23 gene is a missense variant predicted to cause substitution of asparagine to serine at amino acid 2289 (p.Asn2289Ser). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.534, which is neither above nor below the thresholds predicting a damaging or benign impact. This variant was reported in two individuals with sensorineural hearing loss and one individual with postlingual deafness and bilateral vestibular areflexia (LMM unpublished data SCV000271567.2, ARUP Labs unpublished data SCV000602954.2, University Hospital of Geneva unpublished data SCV000494445.1). One individual had a second variant of uncertain significance in trans, and one had a second variant of uncertain significance phase unknown (SCV000602954.2, SCV000494445.1) (Does not meet PM3). In summary, due to limited evidence, this variant is classified as a variant of uncertain significance based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss Variant Curation Expert Panel: PM2_supporting. (VCEP specifications version 2.0.0; Dec 21, 2022)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000215740	SCV000271567	uncertain significance	not specified	2016-02-07	criteria provided, single submitter	clinical testing	The p.Asn2289Ser variant in CDH23 has not been previously reported in individual s with hearing loss and was absent from large population studies. Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine patho genicity. In summary, the clinical significance of the p.Asn2289Ser variant is u ncertain.
Center of Genomic medicine, Geneva, University Hospital of Geneva	RCV000416514	SCV000494445	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 12	2016-06-08	criteria provided, single submitter	clinical testing	This CDH23 heterozygous variant inherited from the mother was found in combination with an another CDH23 heterozygous mutation (presumably inherited from the father, but this could not be ascertained, see above) in a child with bilateral postlingual deafness and bilateral vestibular areflexia
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000755232	SCV000602954	uncertain significance	not provided	2017-05-30	criteria provided, single submitter	clinical testing
Invitae	RCV000755232	SCV004524576	uncertain significance	not provided	2023-11-24	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 2289 of the CDH23 protein (p.Asn2289Ser). This variant is not present in population databases (gnomAD no frequency). 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: 228500). 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.