rs876657754

Positions:

• chr10-71511163-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 5 ACMG points: 5P and 0B. PM2_Supporting PM3 PP3 PP4

This summary comes from the ClinGen Evidence Repository: The c.380A>G (NM_022124.6(CDH23):c.380A>G (p.Asp127Gly)) variant in CDH23 is a missense variant predicted to cause substitution of aspartate by glycine at amino acid 127. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.796 which is above the threshold of 0.7, evidence that correlates with impact to CDH23 function (PP3). This variant has been detected in one individual with autosomal recessive Usher syndrome. For this individual, they were compound heterozygous for the variant and a pathogenic variant (NM_022124.6(CDH23):c.1949dup (p.Leu651fs) (SCV000271345.2) ) and this individual was confirmed in trans by family testing (1.0 point, PM3; LMM internal data). The patient with the variant had congenital severe-profound hearing loss with vestibular complications and ophthalmology-related issues, features highly specific to Usher syndrome (LMM Internal Data; PP4). This variant was re-reviewed on 1.18.2023 and because no additional evidence is available, professional judgment was used to retain this variant as likely pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP. In summary, this variant is classified as likely pathogenic for autosomal recessive Usher Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM2_supporting, PP3, PM3, PP4 (ClinGen Hearing Loss VCEP Specifications Version 2; 6/27/2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10576804/MONDO:0019501/005

• Frequency: Genomes: not found (cov: 33)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 7.68

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-AS1 (HGNC:31433): (CDH23 antisense RNA 1)

ACMG classification

Verdict is Likely_pathogenic. Variant got 5 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH23	NM_022124.6	c.380A>G	p.Asp127Gly	missense_variant	6/70	ENST00000224721.12	NP_071407.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.380A>G	p.Asp127Gly	missense_variant	6/70	5	NM_022124.6	ENSP00000224721.9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 41

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

Usher syndrome Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Jun 27, 2023

The c.380A>G (NM_022124.6(CDH23):c.380A>G (p.Asp127Gly)) variant in CDH23 is a missense variant predicted to cause substitution of aspartate by glycine at amino acid 127. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.796 which is above the threshold of 0.7, evidence that correlates with impact to CDH23 function (PP3). This variant has been detected in one individual with autosomal recessive Usher syndrome. For this individual, they were compound heterozygous for the variant and a pathogenic variant (NM_022124.6(CDH23):c.1949dup (p.Leu651fs) (SCV000271345.2) ) and this individual was confirmed in trans by family testing (1.0 point, PM3; LMM internal data). The patient with the variant had congenital severe-profound hearing loss with vestibular complications and ophthalmology-related issues, features highly specific to Usher syndrome (LMM Internal Data; PP4). This variant was re-reviewed on 1.18.2023 and because no additional evidence is available, professional judgment was used to retain this variant as likely pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP. In summary, this variant is classified as likely pathogenic for autosomal recessive Usher Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM2_supporting, PP3, PM3, PP4 (ClinGen Hearing Loss VCEP Specifications Version 2; 6/27/2022). -

Pituitary adenoma 5, multiple types Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 04, 2024

- -

Autosomal recessive nonsyndromic hearing loss 12 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

King Laboratory, University of Washington

Feb 28, 2023

This variant occurred in compound heterozygosity with a CDH23 missense variant in two siblings with bilateral sensorineural hearing loss of onset <18 years, in a study of pediatric hearing loss conducted by the King Laboratory (Carlson RJ et al. JAMA-OtoHNS 2023). At the time of recruitment, neither sibling had any known visual impairment (ages 13y and 9y). This patient's family has no other history of hearing loss. This variant is a missense at a completely conserved site in a cadherin domain of the CDH23 protein and is predicted to be damaging by multiple in-silico tools. As of January 2023, this variant has been reported previously in an individual with hearing loss and is currently classified as likely pathogenic on ClinVar and is not found on gnomAD. Based on co-segregation with the phenotype in the family, consistently predicted functional effect, previous classification as likely pathogenic, and goodness of fit of genotype to phenotype, we conclude that this variant is likely pathogenic. -

Rare genetic deafness Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 23, 2016

The p.Asp127Gly variant in CDH23 has been identified by our laboratory highly li kely in trans with a pathogenic variant in CDH23 in an individual with clinical features of Usher syndrome (this individual's family). It has not been identifie d in large population studies. Computational prediction tools and conservation a nalysis suggest that this variant may impact the protein, though this informatio n is not predictive enough to determine pathogenicity. The presence of this vari ant in trans with a pathogenic variant in an individual with Usher syndrome incr eases the likelihood that the p.Asp127Gly variant is pathogenic. In summary, alt hough additional studies are required to fully establish its clinical significan ce, this variant is likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T;T;D;.;.;.;T;.;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Pathogenic	3.9	.;.;H;H;.;.;.;.;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-6.0	D;.;D;.;D;.;.;.;.
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D;.;D;.;D;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;.;.
Polyphen		1.0, 1.0	.;.;D;D;.;.;.;.;.
Vest4		0.96
MutPred		0.59		Loss of stability (P = 0.0932);Loss of stability (P = 0.0932);Loss of stability (P = 0.0932);Loss of stability (P = 0.0932);Loss of stability (P = 0.0932);.;Loss of stability (P = 0.0932);Loss of stability (P = 0.0932);.;
MVP		0.92
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.38
gMVP		0.75

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

Publications

LitVar

Other links and lift over

dbSNP: rs876657754; hg19: chr10-73270920;