rs121908354

Variant names:

• chr10-71570884-C-T
• rs121908354
• NM_022124.6:c.719C>T

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM3_Strong PS4 PP1_Strong PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The allele frequency of the c.719C>T (p.Pro240Leu) variant in the CDH23 gene is 0.05% (10/17246) of East Asian chromosomes by gnomAD, which is a low enough frequency to apply PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_Supporting). This variant has been reported in > 10 probands with hearing loss without evidence of retinal disease, including >5 homozygotes, at least 1 compound heterozygote with c.6712+1G>A variant, and >5 compound heterozygotes with rare variants of uncertain significance (PM3_Strong; PMID:24164807, 24618850, 25963016, 26264712, 17850630, 22899989). This variant has also segregated in 3 siblings with hearing loss (PP1_Strong, PMID:17850630, 22899989). The variant was identified in the heterozygous state in a patient with Usher syndrome who also harbored a homozygous missense variant in MYO7A (PMID:24618850). A case-control meta analysis found that the p.Pro240Leu variant was associated with a 12-fold higher risk of hearing loss compared to the wild-type allele (OR = 11.68; 95% CI = 3.16–43.24; PS4), though it should be noted that it appears that some probands were included in more than one study included in the meta-analysis (PMID 30367262). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PP1_Strong, PM3_Strong, PM2_Supporting, PS4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA253338/MONDO:0019497/005

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000035 (0 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:10 U:1
• Conservation: PhyloP100: 7.28
• Publications: 37 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

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6	c.719C>T	p.Pro240Leu	missense_variant	Exon 8 of 70	ENST00000224721.12	NP_071407.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.719C>T	p.Pro240Leu	missense_variant	Exon 8 of 70	5	NM_022124.6	ENSP00000224721.9

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152234 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000401 AC: 10 AN: 249236 AF XY: 0.0000296

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000556

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000349 AC: 51 AN: 1461668 Hom.: 0 Cov.: 32 AF XY: 0.0000330 AC XY: 24 AN XY: 727120

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00128 AC: 51 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111844

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152352 Hom.: 0 Cov.: 33 AF XY: 0.0000268 AC XY: 2 AN XY: 74494

African (AFR) AF: 0.00 AC: 0 AN: 41586

American (AMR) AF: 0.00 AC: 0 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000135 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000908 AC: 11

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 12 Pathogenic:4

Oct 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jul 01, 2017

Division of Hearing and Balance Research, National Hospital Organization Tokyo Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 14, 2018

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Across a selection of the available literature, the CDH23 c.719C>T (p.Pro240Leu) missense variant has been identified in a homozygous state in nine affected individuals, in a compound heterozygous state in 20 affected individuals, and in a heterozygous state in 21 affected individuals. The phenotypic spectrum of these patients varied from mild to profound hearing loss, with age of onset ranging from infant to adult onset, with the majority presenting with bilateral hearing loss (Wagatsuma et al. 2007; Miyagawa et al. 2012; Miyagawa et al. 2013; Kim et al. 2015). One patient who was heterozygous for the p.Pro240Leu variant, was diagnosed with Usher syndrome. This individual also carried a homozygous missense variant in the MYO7A gene (Yoshimura et al. 2014). Of the 21 affected heterozygotes with hearing loss, 19 were reported in a study where the second allele may not have been ascertained due to limitations of a genotyping assay; five were from families with at least two affected generations but segregation of the variant was not demonstrated by the authors (Miyagawa et al. 2012). Variants in CDH23 have not been historically reported in association with dominant hearing loss, however a dominant presentation cannot be ruled out in these families. The p.Pro240Leu variant was reported in two of 676 controls in a heterozygous state and is reported at a frequency of 0.001276 in the East Asian population of the Exome Aggregation Consortium database. Based on the collective evidence, the p.Pro240Leu variant is classified as pathogenic for autosomal recessive nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Jan 03, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 30367262, PS4_S) and co-segregated with Deafness, autosomal recessive 12 in multiple affected family members with additional meioses meeting strong evidence levels (PMID: 17850630, 22899989, PP1_S). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals(PMID: 24164807, 24618850, 25963016, 26264712, 17850630, 22899989, PM3_S). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000040, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:2

Jul 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 240 of the CDH23 protein (p.Pro240Leu). This variant is present in population databases (rs121908354, gnomAD 0.06%). This missense change has been observed in individual(s) with non-syndromic hearing loss (PMID: 17850630, 22443853, 22899989, 23967202, 24767429, 25279224, 25963016, 26264712, 26763877, 27583405, 27792758). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4928). 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 with a negative predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

May 27, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 26763877, 24164807, 30367262, 25963016, 27792758, 24767429, 26264712, 17850630, 23967202, 24618850, 22899989) -

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

Apr 11, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pituitary adenoma 5, multiple types Pathogenic:1

Mar 29, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nonsyndromic genetic hearing loss Pathogenic:1

Jul 22, 2019

ClinGen Hearing Loss Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The allele frequency of the c.719C>T (p.Pro240Leu) variant in the CDH23 gene is 0.05% (10/17246) of East Asian chromosomes by gnomAD, which is a low enough frequency to apply PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_Supporting). This variant has been reported in > 10 probands with hearing loss without evidence of retinal disease, including >5 homozygotes, at least 1 compound heterozygote with c.6712+1G>A variant, and >5 compound heterozygotes with rare variants of uncertain significance (PM3_Strong; PMID:24164807, 24618850, 25963016, 26264712, 17850630, 22899989). This variant has also segregated in 3 siblings with hearing loss (PP1_Strong, PMID: 17850630, 22899989). The variant was identified in the heterozygous state in a patient with Usher syndrome who also harbored a homozygous missense variant in MYO7A (PMID: 24618850). A case-control meta analysis found that the p.Pro240Leu variant was associated with a 12-fold higher risk of hearing loss compared to the wild-type allele (OR = 11.68; 95% CI = 3.16–43.24; PS4), though it should be noted that it appears that some probands were included in more than one study included in the meta-analysis (PMID 30367262). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PP1_Strong, PM3_Strong, PM2_Supporting, PS4. -

Usher syndrome type 1 Pathogenic:1

Feb 06, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Usher syndrome type 1D Uncertain:1

Jul 18, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Uncertain	0.062	T
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.056	T;T;T;.;.;.;T;.;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.38	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	1.3	.;.;L;L;.;.;.;.;.
PhyloP100		7.3
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-6.7	D;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.52
Sift	Uncertain	0.0010	D;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.0050	D;D;.;T;D;D;D;.;.
Polyphen		0.82, 1.0	.;.;P;D;.;.;.;.;.
Vest4		0.88
MVP		0.85
ClinPred		0.51	D
GERP RS		5.2
PromoterAI		-0.016	Neutral
Varity_R		0.43
gMVP		0.56
Mutation Taster		=8/92	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs121908354; hg19: chr10-73330641;