Submissions for variant NM_022124.6(CDH23):c.5248G>A (p.Gly1750Arg)

gnomAD frequency: 0.00005  dbSNP: rs372822465

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000039206	SCV000062890	uncertain significance	not specified	2011-01-09	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The Gly1750Arg variant in CDH23 has not been reported in the literature nor previously identifi ed by our laboratory. This residue is conserved across species and computational analyses (PolyPhen2, SIFT, AlignGVGD) suggest that the Gly1750Arg variant may i mpact the protein. However, this information is not predictive enough to assume pathogenicity. It should be noted that this lab has only sequenced the CDH23 in 94 Caucasian individuals such that the full spectrum of benign variation has not yet been defined for this gene, increasing the possibility that this may be a b enign variant. In summary, the clinical significance of this variant cannot be d etermined with certainty at this time.
Illumina Laboratory Services, Illumina	RCV000309122	SCV000363784	uncertain significance	Autosomal recessive nonsyndromic hearing loss 12	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000340535	SCV000363785	uncertain significance	Usher syndrome type 1D	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae	RCV002513529	SCV003299012	uncertain significance	not provided	2022-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1750 of the CDH23 protein (p.Gly1750Arg). This variant is present in population databases (rs372822465, gnomAD 0.006%). 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: 45971). 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.
Natera, Inc.	RCV001274890	SCV001459443	uncertain significance	Usher syndrome type 1	2020-09-16	no assertion criteria provided	clinical testing