Submissions for variant NM_022124.6(CDH23):c.4021G>A (p.Asp1341Asn)

dbSNP: rs121908351

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000436619	SCV000521016	likely pathogenic	not provided	2022-12-12	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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: 12075507, 19683999, 16963483, 12786748, 21940737, 31589614, 35020051, 15353998, 12522556)
Invitae	RCV000436619	SCV001587038	pathogenic	not provided	2023-12-23	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1341 of the CDH23 protein (p.Asp1341Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal recessive non-syndromic hearing loss and with Usher syndrome (PMID: 12522556, 19683999). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4923). 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. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV003472977	SCV004210665	likely pathogenic	Pituitary adenoma 5, multiple types	2023-06-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003492284	SCV004241862	pathogenic	Usher syndrome	2023-12-05	criteria provided, single submitter	clinical testing	Variant summary: CDH23 c.4021G>A (p.Asp1341Asn) results in a conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 245970 control chromosomes. c.4021G>A has been reported at a compound heterozygous state along with different pathogenic variants in CDH23 in multiple individuals affected with autosomal recessive hearing loss (example, Usami_2022, deBrouwer_2003). These data indicate that the variant is very likely to be associated with disease. 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: 35020051, 12522556). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000005205	SCV000025382	pathogenic	Autosomal recessive nonsyndromic hearing loss 12	2003-02-01	no assertion criteria provided	literature only
Natera, Inc.	RCV001272891	SCV001455315	likely pathogenic	Usher syndrome type 1	2020-09-16	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000436619	SCV001955527	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000436619	SCV001971108	uncertain significance	not provided		no assertion criteria provided	clinical testing