rs397517323

Positions:

• chr10-71725422-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_022124.6(CDH23):​c.3481C>T​(p.Arg1161*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000274 in 1,461,700 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CDH23 NM_022124.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 3.64

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]

C10orf105 (HGNC:20304): (chromosome 10 open reading frame 105) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

CDH23 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-71725422-C-T is Pathogenic according to our data. Variant chr10-71725422-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 45920.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-71725422-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH23	NM_022124.6	c.3481C>T	p.Arg1161*	stop_gained	30/70	ENST00000224721.12	NP_071407.4
CDH23	NM_001171930.2	c.3481C>T	p.Arg1161*	stop_gained	30/32		NP_001165401.1
C10orf105	NM_001168390.2	c.-5-9080G>A		intron_variant			NP_001161862.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.3481C>T	p.Arg1161*	stop_gained	30/70	5	NM_022124.6	ENSP00000224721.9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461700 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727130

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pituitary adenoma 5, multiple types Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 16, 2023

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 13, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 45920). This premature translational stop signal has been observed in individual(s) with Usher syndrome (PMID: 16679490). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg1161*) in the CDH23 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CDH23 are known to be pathogenic (PMID: 11138009, 21940737). -

Hearing loss, autosomal recessive Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

-

- -

Autosomal recessive nonsyndromic hearing loss 12 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

3billion

Sep 01, 2022

The variant is not observed in the gnomAD v2.1.1 dataset. Stop-gained (nonsense) is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported to be associated with CDH23-related disorder (ClinVar ID: VCV000045920 / PMID: 16679490). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Rare genetic deafness Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 15, 2011

The p.Arg1161X variant in CDH23 has been reported in the homozygous state in one individual with Usher syndrome (Roux 2006). It has also been previously identif ied by our laboratory in an individual with Usher syndrome who carried the varia nt in compound heterozygosity with another pathogenic CDH23 variant. The p.Arg11 61X variant leads to a premature stop codon at position 1161, which is predicted to lead to a truncated or absent protein. In summary, this variant meets our cr iteria to be classified as pathogenic for Usher syndrome in an autosomal recessi ve manner. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	43
DANN	Uncertain	1.0
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.91	D
Vest4		0.94
GERP RS		5.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs397517323; hg19: chr10-73485179; COSMIC: COSV56481779;