Submissions for variant NM_022124.6(CDH23):c.2926A>G (p.Ser976Gly)

gnomAD frequency: 0.00016  dbSNP: rs372401651

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000614964	SCV000710985	uncertain significance	not specified	2016-12-08	criteria provided, single submitter	clinical testing	The p.Ser976Gly variant in CDH23 has not been previously reported in individuals with hearing loss or Usher syndrome, but has been identified in 21/62086 Europe an chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinsti tute.org; dbSNP rs372401651). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Com putational prediction tools and conservation analyses do not provide strong supp ort for or against an impact to the protein. In summary, the clinical significan ce of the p.Ser976Gly variant is uncertain.
Invitae	RCV001244820	SCV001418064	uncertain significance	not provided	2022-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 976 of the CDH23 protein (p.Ser976Gly). This variant is present in population databases (rs372401651, gnomAD 0.03%). 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: 504554). 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) performed at Invitae indicates that this missense variant is not expected to disrupt 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.
GeneDx	RCV001244820	SCV001766753	uncertain significance	not provided	2021-06-15	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; 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: 27535533)
Genome-Nilou Lab	RCV001559178	SCV001781268	uncertain significance	Autosomal recessive nonsyndromic hearing loss 12	2021-07-14	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001559179	SCV001781269	uncertain significance	Usher syndrome type 1D	2021-07-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002532715	SCV003679163	uncertain significance	Inborn genetic diseases	2021-08-17	criteria provided, single submitter	clinical testing	The c.2926A>G (p.S976G) alteration is located in exon 25 (coding exon 24) of the CDH23 gene. This alteration results from a A to G substitution at nucleotide position 2926, causing the serine (S) at amino acid position 976 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001244820	SCV001962774	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001244820	SCV001965313	uncertain significance	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001834918	SCV002089901	uncertain significance	Usher syndrome type 1	2019-10-28	no assertion criteria provided	clinical testing