Submissions for variant NM_022124.6(CDH23):c.2959G>A (p.Asp987Asn)

gnomAD frequency: 0.00002  dbSNP: rs770665588

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001339975	SCV001533760	uncertain significance	not provided	2021-08-13	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid with asparagine at codon 987 of the CDH23 protein (p.Asp987Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs770665588, ExAC 0.06%). This missense change has been observed in individual(s) with autosomal recessive non-syndromic hearing loss (PMID: 26226137; Invitae). 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 C15"). 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.
GeneDx	RCV001339975	SCV001988124	uncertain significance	not provided	2022-12-21	criteria provided, single submitter	clinical testing	Observed with a second CDH23 variant in an individual with hearing loss in published literature (Bademci et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26226137, 34652575)
King Laboratory, University of Washington	RCV003155398	SCV003844197	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 12	2023-02-28	criteria provided, single submitter	research	This variant occurred in compound heterozygosity with a CDH23 frameshift variant in a patient with bilateral sensorineural hearing loss of onset <18 years, in a study of pediatric hearing loss conducted by the King Laboratory (Carlson RJ et al. JAMA-OtoHNS 2023). At the time of recruitment, this patient did not have any known visual impairment (age 6y). This patient's family has no other history of hearing loss. This variant is a missense at a completely conserved site and is predicted to be damaging by multiple in-silico tools. As of January 2023, this variant has not been reported to ClinVar and is not found on gnomAD. Based on compound heterozygosity with a loss-of-function variant, consistently predicted functional effect, and goodness of fit of genotype to phenotype, we conclude that this variant is likely pathogenic.
Baylor Genetics	RCV003473868	SCV004210633	likely pathogenic	Pituitary adenoma 5, multiple types	2023-08-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003490201	SCV004240991	uncertain significance	not specified	2023-12-12	criteria provided, single submitter	clinical testing	Variant summary: CDH23 c.2959G>A (p.Asp987Asn) results in a conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.8e-05 in 224614 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2959G>A has been reported in the literature as a single heterozygous change in one individual affected with autosomal recessive hearing loss, without strong evidence for causality (example, Bademci_2015). These report(s) 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 publication have been ascertained in the context of this evaluation (PMID: 26226137). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (Likely pathogenic, n=1; VUS, n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.