10-71812822-C-T

Variant names:

• chr10-71812822-C-T
• rs121908353
• NM_022124.6:c.9565C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

This summary comes from the ClinGen Evidence Repository: The c.9565C>T variant in CDH23 is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 3189. The only evidence resulting in a classification code was determined by the computational predictor REVEL which gives a score of 0.783, which is above the threshold of 0.7, evidence that correlates with impact to CDH23 function (PP3). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00039 (4/10320 alleles) in the Ashkenazi Jewish population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PP3 (ClinGen Hearing Loss VCEP specifications version 2; 6/15/2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA117145/MONDO:0019501/005

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:6 O:1
• Conservation: PhyloP100: 3.12
• Publications: 5 publications found

Genes affected

CDH23 (HGNC:13733): (cadherin related 23) This gene is a member of the cadherin superfamily, whose genes encode calcium dependent cell-cell adhesion glycoproteins. The encoded protein is thought to be involved in stereocilia organization and hair bundle formation. The gene is located in a region containing the human deafness loci DFNB12 and USH1D. Usher syndrome 1D and nonsyndromic autosomal recessive deafness DFNB12 are caused by allelic mutations of this cadherin-like gene. Upregulation of this gene may also be associated with breast cancer. Alternative splice variants encoding different isoforms have been described. [provided by RefSeq, May 2013]

CDH23 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 12

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Usher syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Usher syndrome type 1D

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LOC124902446 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022124.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	NM_022124.6	MANE Select	c.9565C>T	p.Arg3189Trp	missense	Exon 68 of 70	NP_071407.4
	CDH23	NM_001171933.1		c.2845C>T	p.Arg949Trp	missense	Exon 21 of 23	NP_001165404.1
	CDH23	NM_001171934.1		c.2845C>T	p.Arg949Trp	missense	Exon 21 of 22	NP_001165405.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.9565C>T	p.Arg3189Trp	missense	Exon 68 of 70	ENSP00000224721.9
	CDH23	ENST00000398788.4	TSL:1	c.2845C>T	p.Arg949Trp	missense	Exon 21 of 23	ENSP00000381768.3
	CDH23	ENST00000619887.4	TSL:1	c.2845C>T	p.Arg949Trp	missense	Exon 21 of 22	ENSP00000478374.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152232 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.0000161 AC: 4 AN: 247794 AF XY: 0.0000149

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000399

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461110 Hom.: 0 Cov.: 37 AF XY: 0.0000165 AC XY: 12 AN XY: 726794

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44608

Ashkenazi Jewish (ASJ) AF: 0.000306 AC: 8 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86130

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111594

Other (OTH) AF: 0.0000663 AC: 4 AN: 60352

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152232 Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5 AN XY: 74370

African (AFR) AF: 0.0000482 AC: 2 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.000479 AC: 1 AN: 2086

Alfa AF: 0.0000287 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.00000826 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000595

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:6 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:2

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CDH23 p.Arg86Trp variant was not identified in the Cosmic database but was identified in dbSNP (ID: rs121908353) ClinVar (reported as a VUS by Partners Laboratory for Molecular Medicine), Clinvitae, MutDB and LOVD 3.0. The variant was identified in control databases in 6 of 279194 chromosomes at a frequency of 0.000021 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 4 of 10320 chromosomes (freq: 0.000388) and African in 2 of 24024 chromosomes (freq: 0.000083); it was not observed in the Latino, East Asian, European (Finnish), European (non-Finnish), Other, and South Asian populations. Zheng et al. (2005) identified the variant in a proband with deafness who also carried a PCDH15 variant. The p.Arg86 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

Jul 06, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 3189 of the CDH23 protein (p.Arg3189Trp). This variant is present in population databases (rs121908353, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of CDH23-related conditions (PMID: 15537665, 15660226). ClinVar contains an entry for this variant (Variation ID: 4926). 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 C0"). 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.

Usher syndrome type 1 Uncertain:1 Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Sep 16, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

USHER SYNDROME, TYPE ID/F, DIGENIC Pathogenic:1

Jan 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Autosomal recessive nonsyndromic hearing loss 12;C1832845:Usher syndrome type 1D;C4539685:Pituitary adenoma 5, multiple types Uncertain:1

Jan 19, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Uncertain:1

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Benign. The Arg3189Trp vari ant (CDH23) has been reported in the literature twice and was absent from 200 co ntrols (Zheng 2005, Ouyang 2005). However, we suspect that the two reports were not independent and represent the same patient, who may also represent the prese nt patient, based upon the co-occurrence of this variant and the Tyr16fs variant noted in one of the papers. Computational analyses (biochemical amino acid prop erties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong supp ort for or against an impact to the protein. In summary, the clinical significan ce of this variant cannot be determined with certainty at this time.

Usher syndrome Uncertain:1

Jul 02, 2025

ClinGen Hearing Loss Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The c.9565C>T variant in CDH23 is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 3189. The only evidence resulting in a classification code was determined by the computational predictor REVEL which gives a score of 0.783, which is above the threshold of 0.7, evidence that correlates with impact to CDH23 function (PP3). The highest population minor allele frequency in gnomAD v4.1 is 0.000338 (10/29592) in the Ashkenazi Jewish Population (PM2_Supporting and BS1_Supporting are not met). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PP3 (ClinGen Hearing Loss VCEP specifications version 2; 6/30/2025).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.024	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Benign	1.0	L
PhyloP100		3.1
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-2.4	N
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.88		Gain of sheet (P = 0.039)
MVP		0.92
MPC		0.47
ClinPred		0.88	D
GERP RS		4.9
Varity_R		0.79
gMVP		0.71
Mutation Taster		=3/97	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs121908353; hg19: chr10-73572579;