rs397517349

Positions:

chr10-71793542-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM3PP1PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The variant c.6614C>T (NM_022124.6(CDH23):c.6614C>T (p.Pro2205Leu)) in CDH23 is a missense variant predicted to cause substitution of proline by leucine at amino acid 2205 (p.Pro2205Leu). The highest population minor allele frequency in gnomAD v4.0.0 is 0.000002920 (8/1179896 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.00007) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.342, which is neither above nor below the thresholds predicting a damaging or benign impact on CDH23 function. This variant has been detected in at least 8 individuals with autosomal recessive hearing loss. All of these individuals were homozygous for the variant (1.0 pts; PMIDs: 28501645, 32747562 & LMM Internal Data (SCV000062934.5); PM3). There was a common haplotype found between five affected individuals from three families, one of which had three affected siblings, including a set of twins. Personal communication confirmed the three siblings were sequenced; however, it was not apparent whether the twins were dizygotic or monozygotic and therefore only one twin was counted toward segregation (PP1_Supporting; 28501645). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Usher syndrome, based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP (PM2_Supporting, PM3, PP1_Supporting; Version 2; 11/15/23). LINK:https://erepo.genome.network/evrepo/ui/classification/CA137541/MONDO:0019501/005

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:5U:5

Conservation

PhyloP100: 6.12

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

PM3

PP1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH23	NM_022124.6 linkuse as main transcript	c.6614C>T	p.Pro2205Leu	missense_variant	48/70	ENST00000224721.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12 linkuse as main transcript	c.6614C>T	p.Pro2205Leu	missense_variant	48/70	5	NM_022124.6	P1	Q9H251-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

248748

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134958

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000887

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461514

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727042

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:5Uncertain:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Usher syndrome

Pathogenic:1Uncertain:1

Uncertain significance, reviewed by expert panel	curation	ClinGen Hearing Loss Variant Curation Expert Panel	Nov 15, 2023	The variant c.6614C>T (NM_022124.6(CDH23):c.6614C>T (p.Pro2205Leu)) in CDH23 is a missense variant predicted to cause substitution of proline by leucine at amino acid 2205 (p.Pro2205Leu). The highest population minor allele frequency in gnomAD v4.0.0 is 0.000002920 (8/1179896 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.00007) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.342, which is neither above nor below the thresholds predicting a damaging or benign impact on CDH23 function. This variant has been detected in at least 8 individuals with autosomal recessive hearing loss. All of these individuals were homozygous for the variant (1.0 pts; PMIDs: 28501645, 32747562 & LMM Internal Data (SCV000062934.5); PM3). There was a common haplotype found between five affected individuals from three families, one of which had three affected siblings, including a set of twins. Personal communication confirmed the three siblings were sequenced; however, it was not apparent whether the twins were dizygotic or monozygotic and therefore only one twin was counted toward segregation (PP1_Supporting; 28501645). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Usher syndrome, based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP (PM2_Supporting, PM3, PP1_Supporting; Version 2; 11/15/23). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 05, 2023	Variant summary: CDH23 c.6614C>T (p.Pro2205Leu) 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 4e-06 in 248748 control chromosomes (gnomAD v2), absent in 316 control individuals from Middle Eastern (gnomAD v3) and absent in 1309 Palestinian controls (Rayyan _2020). c.6614C>T has been reported in the literature in multiple individuals affected with Non-syndromic hearing loss, including being seen phase unknown along with a VUS missense in a sporadic case (Sloan_Heggen_2016), in homozygous state in 5 patients from 3 consanguineous pedigrees in Qatar (Alkowari_2017), and in homozygous state in 2 patients from 2 Palestinian families (Rayyan _2020). Haplotype analysis of the patients revealed a same haplotype across those patients from Qatar, which support a common ancestor in those patients or a founder effect of this variant (Alkowari_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28501645, 29048421, 32747562, 26969326). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 among which four (including the ClinGen Hearing Loss Variant Curation Expert Panel) classified the variant as VUS, and one as likely pathogenic. Some submitters classifying the variant as uncertain significance cited the expert panel assertion and cited overlapping but not identical evidence captured in the context of this ascertainment. Based on the additional emerging evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 22, 2023	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: 25356970, 34426522, 31860473, 34338889, 32747562, 26969326, 28501645) -
Likely pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	-	- -

Autosomal recessive nonsyndromic hearing loss 12

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	research	King Laboratory, University of Washington	Aug 01, 2020	CDH23 c.6614C>T, p.E1071K alters a highly conserved residue of CDH23. The variant is homozygous in 3 children from 2 Palestinian families with moderate pre-lingual hearing loss (Abu Rayyan 2020). It was found also in 6 Palestinian children in compound heterozygosity with CDH23 c.1675C>T. The variant is absent from 1300 Palestinian controls and from gnomAD v2.1.1. This variant was previously interpreted as a VUS by the Expert Panel due to few Arab population controls. We suggest reclassification to LP given perfect co-segregation with hearing loss in additional families (both as a homozygote and as a compound heterozygote) and its absence from 1300 ancestry-matched controls -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 23, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Pituitary adenoma 5, multiple types

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 14, 2024

- -

Usher syndrome type 1D

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Overall WES conclusion for patient, including all identified alterations: Uncertain -

Rare genetic deafness

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 02, 2023

The p.Pro2205Leu variant in CDH23 has been reported in 3 individuals with hearing loss and 1 individual with Usher syndrome, 3 of whom were of Middle Eastern ancestry (Syrian, Saudi Arabian, Kuwaiti; Sloan-Heggen 2016, LMM data). Of the three individuals with hearing loss, one was homozygous, one individual was heterozygous, and one was compound heterozygous with a second CDH23 variant of uncertain significance. The individual with Usher syndrome was homozygous for a pathogenic variant in another gene that could account for the disease. This variant was absent from large population studies, though none of these studies specify frequency data for individuals of Middle Eastern ancestry. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM3_supporting. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.073

T;T

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.95

D;D

M_CAP

Benign

0.083

MetaRNN

Pathogenic

0.77

D;D

MetaSVM

Benign

-0.29

MutationAssessor

Uncertain

2.1

.;M

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.52

REVEL

Uncertain

0.34

Sift4G

Pathogenic

0.0

D;.

Polyphen

1.0

.;D

Vest4

0.85

MutPred

0.51

Gain of ubiquitination at K2206 (P = 0.0898);Gain of ubiquitination at K2206 (P = 0.0898);

MVP

0.72

ClinPred

0.97

GERP RS

5.1

Varity_R

0.61

gMVP

0.65

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over