rs1060499791

Variant names:

• chr10-71617295-C-T
• rs1060499791
• NM_022124.6:c.1036C>T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_022124.6(CDH23):​c.1036C>T​(p.Pro346Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P346L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.44
• Publications: 3 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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-71617296-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 402251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.912
• PP5: Variant 10-71617295-C-T is Pathogenic according to our data. Variant chr10-71617295-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 402250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6	c.1036C>T	p.Pro346Ser	missense_variant	Exon 11 of 70	ENST00000224721.12	NP_071407.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.1036C>T	p.Pro346Ser	missense_variant	Exon 11 of 70	5	NM_022124.6	ENSP00000224721.9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 12 Pathogenic:3

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 01, 2020

King Laboratory, University of Washington

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

CDH23 c.1036C>T, p.P346S alters a highly conserved residue of CDH23. The variant is homozygous in 8 children from 3 Palestinian families with pre-lingual hearing loss (Abu Rayyan 2020). The variant is absent from 1300 Palestinian controls and from gnomAD v2.1.1. -

Jun 04, 2016

Hereditary Research Laboratory, Bethlehem University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

not provided Pathogenic:1

Jul 28, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro346Leu amino acid residue in CDH23. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19888295). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 expected to disrupt CDH23 protein function. ClinVar contains an entry for this variant (Variation ID: 402250). This missense change has been observed in individual(s) with deafness (PMID: 19888295). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 346 of the CDH23 protein (p.Pro346Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.40
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.25	T;T;D;.;.;.;T;.;.
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.1	.;.;H;H;.;.;.;.;.
PhyloP100		7.4
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-6.8	D;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.018	D;D;.;D;D;D;D;.;.
Polyphen		1.0	.;.;D;D;.;.;.;.;.
Vest4		0.96
MutPred		0.52		Loss of catalytic residue at P346 (P = 0.0604);Loss of catalytic residue at P346 (P = 0.0604);Loss of catalytic residue at P346 (P = 0.0604);Loss of catalytic residue at P346 (P = 0.0604);Loss of catalytic residue at P346 (P = 0.0604);.;Loss of catalytic residue at P346 (P = 0.0604);Loss of catalytic residue at P346 (P = 0.0604);.;
MVP		0.97
ClinPred		1.0	D
GERP RS		5.5
PromoterAI		-0.00010	Neutral
Varity_R		0.85
gMVP		0.88
Mutation Taster		=0/100	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: rs1060499791; hg19: chr10-73377052;