Submissions for variant NM_022124.6(CDH23):c.3074G>A (p.Gly1025Asp)

gnomAD frequency: 0.00358  dbSNP: rs143179070

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000039141	SCV000062825	benign	not specified	2014-07-01	criteria provided, single submitter	clinical testing	Gly1025Asp in Exon 26A of CDH23: This variant is not expected to have clinical s ignificance because it has been identified in 1.0% (42/4324) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs143179070).
Eurofins Ntd Llc (ga)	RCV000039141	SCV000228383	benign	not specified	2015-04-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000839197	SCV000981083	benign	not provided	2019-11-13	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 28847902, 26969326)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000839197	SCV001103624	benign	not provided	2024-01-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001105453	SCV001262417	benign	Usher syndrome type 1D	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV001105454	SCV001262418	uncertain significance	Autosomal recessive nonsyndromic hearing loss 12	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
National Institute on Deafness and Communication Disorders, National Institutes of Health	RCV001328026	SCV001519359	uncertain significance	Childhood onset hearing loss	2021-07-08	criteria provided, single submitter	research	PP3 / Modifications from PMID: 30311386 for classification: The genetic causes of hearing loss have not yet been well characterized in the Yoruba population, and the information regarding variant MAF in this population is still limited, so we did not exclude any variant based on their "high" MAF. PP3 criteria was applied even if the REVEL score was below 0.7, if at least two of the pathogenicity prediction algorithms used predicted that the variant was damaging or likely damaging.
Genome-Nilou Lab	RCV001105453	SCV001652745	likely benign	Usher syndrome type 1D	2021-05-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000039141	SCV002547552	benign	not specified	2022-05-17	criteria provided, single submitter	clinical testing	Variant summary: CDH23 c.3074G>A (p.Gly1025Asp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00093 in 236206 control chromosomes, predominantly at a frequency of 0.012 within the African or African-American subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDH23 causing Usher Syndrome phenotype (0.0032), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign n=6, VUS n=2). Based on the evidence outlined above, the variant was classified as benign.
UAEU Genomics Laboratory, United Arab Emirates University	RCV001105454	SCV003926561	uncertain significance	Autosomal recessive nonsyndromic hearing loss 12	2021-12-21	criteria provided, single submitter	research	The missense variant NM_022124.6(CDH23):c.3074G>A (p.Gly1025Asp) has been reported previously in association with Ushersyndrome 1D in homozygous state (PMID:26969326). The p.Gly1025Asp variant is observed in 164/13,980 (1.1731%) alleles from individuals of gnomAD African background in gnomAD which is higher than expected for the disorder. However the causes of hearing loss in the middle Eastern population is not well characterized and therefore this variant cannot be excluded based on high MAF. There is a moderate physicochemical difference between glycine and aspartic acid. The p.Gly1025Asp missense variant is predicted to be damaging by both SIFT and PolyPhen2. For these reasons, this variant has been classified as Uncertain Significance. In this patient this variant is inherited from the Father. The patient carries another variant in the same gene, inherited from the mother. In summary the currently available information is insufficient to determine the clinical significance of this variant. Therefore it has been classified as uncertain significance
CeGaT Center for Human Genetics Tuebingen	RCV000839197	SCV004699715	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	CDH23: BS1
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV001105453	SCV004807275	uncertain significance	Usher syndrome type 1D	2024-03-26	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001272552	SCV001454644	benign	Usher syndrome type 1	2020-01-27	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004534828	SCV004756564	benign	CDH23-related disorder	2020-03-02	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).