rs111033536

chr10-71812826-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_022124.6(CDH23):c.9569C>T(p.Ala3190Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000487 in 1,613,470 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★).

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00050 (0 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:8 B:1
• Conservation: PhyloP100: 7.85

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]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.41023725).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH23	NM_022124.6	c.9569C>T	p.Ala3190Val	missense_variant	68/70	ENST00000224721.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12	c.9569C>T	p.Ala3190Val	missense_variant	68/70	5	NM_022124.6	P1

Frequencies

GnomAD3 genomes AF: 0.000361 AC: 55 AN: 152264 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000617

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000339 AC: 84 AN: 247998 Hom.: 0 AF XY: 0.000379 AC XY: 51 AN XY: 134614

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000378

Gnomad ASJ exome AF: 0.000698

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.000543

Gnomad OTH exome AF: 0.000332

GnomAD4 exome AF: 0.000500 AC: 731 AN: 1461206 Hom.: 0 Cov.: 38 AF XY: 0.000488 AC XY: 355 AN XY: 726848

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000403

Gnomad4 ASJ exome AF: 0.000727

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000587

Gnomad4 OTH exome AF: 0.000613

GnomAD4 genome AF: 0.000361 AC: 55 AN: 152264 Hom.: 0 Cov.: 33 AF XY: 0.000363 AC XY: 27 AN XY: 74384

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000617

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000546 Hom.: 0

Bravo AF: 0.000348

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000237 AC: 2

ExAC AF: 0.000273 AC: 33

EpiCase AF: 0.000491

EpiControl AF: 0.000773

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:8 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 17, 2022	Identified in a patient with nonsyndromic hearing loss, along with a second variant with unknown phase in published literature (Sommen et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25404053, 27068579, 30245029, 32387678) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 20, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	CDH23: PP3 -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 13, 2023	Variant summary: CDH23 c.9569C>T (p.Ala3190Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00034 in 247998 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CDH23 causing Usher Syndrome (0.00034 vs 0.0032), allowing no conclusion about variant significance. c.9569C>T has been reported in the literature in individuals with hearing loss (e.g., Aparisi_2014, Sommen_2016, Clabout_2022), however without strong evidence of causality in all cases (e.g., lack of a second confirmed CDH23 allele and/or segregation/phase not determined). This variant was also listed as an expert curated classification of "likely pathogenic" in the Deafness Variation Database (DVD) (e.g., Azaiez_2018) and cited by others (e.g., Chen_2019). These reports therefore do not provide unequivocal conclusions about association of the variant with Usher Syndrome. 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: 25404053, 30245029, 27068579, 36672845, 31445392). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS, n=6; Likely pathogenic, n=1; Benign, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 12, 2017	The p.Ala3190Val variant in CDH23 has been reported in 1 individual with Usher s yndrome who also had a duplication of exon 29 in CDH23 that is of uncertain sign ificance (Aparisi 2014), and in 1 individual with hearing loss who also had the p.Arg3206Cys variant of uncertain significance in CDH23 (Sommen 2016). The p.Ala 3190Val variant has also been identified by our laboratory in the heterozygous s tate in 3 individuals with hearing loss; however, a variant affecting the remain ing copy of CDH23 was not identified in any of these individuals. This variant h as been identified in 0.08% (8/10122) of Ashkenazi Jewish chromosomes and 0.05% (64/126200) European chromosomes by Genome Aggregation Database (gnomAD, http:// gnomad.broadinstitute.org; dbSNP rs111033536). Although this variant has been se en in the general population, its frequency is not high enough to rule out a pat hogenic role. Computational prediction tools and conservation analyses suggest t hat this variant may impact the protein, though this information is not predicti ve enough to determine pathogenicity. In summary, the clinical significance of t he p.Ala3190Val variant is uncertain. -

Hearing impairment Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center

Apr 12, 2021

PS1_Moderate, PM2_Moderate, PP3_Supporting -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 04, 2022

- -

Pituitary adenoma 5, multiple types Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 30, 2023

- -

Usher syndrome Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Nov 15, 2023

The c.9569C>T variant (NM_022124.6(CDH23):c.9569C>T (p.Ala3190Val)) in CDH23 is a missense variant predicted to cause substitution of alanine by valine at amino acid 3190 (p.Ala3190Val). The highest minor allele frequency in gnomAD v4.0.0 is 694/1179698 alleles (0.0005517), in the European (non-Finnish) population (no population codes met). This variant has been observed in a homozygous state in one parent reported to have no features of Usher syndrome (BS2; Invitae internal data; ClinVar SCV001110059.2). The computational predictor REVEL gives a score of 0.836, which is above the Hearing Loss VCEP threshold of 0.7, evidence that correlates with impact to CDH23 function (PP3). The variant was found in a compound heterozygous state with a deletion of exon 29, a variant which was not able to be confirmed by aCGH (PMID: 25404053). The variant was also found in an unknown phase with p.Arg3206Cys (c.9616C>T), a variant of uncertain significance, in an affected patient with nonsyndromic hearing loss (PMID: 27068579; PM3 not met). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss Expert Panel: BS2, PP3 (Version 2; 11/15/2023). -

CDH23-Related Disorders Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Dec 05, 2017

The CDH23 c.9569C>T (p.Ala3190Val) missense variant has been reported in two studies in which it is identified in a compound heterozygous state in two individuals, one with a diagnosis of Usher syndrome and one with autosomal recessive nonsyndromic hearing loss (Aparisi et al. 2014; Sommen et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.00047 in the European (non-Finnish) population of the Exome Aggregation Consortium. The evidence for this variant is limited. Based on the evidence, the p.Ala3190Val variant is classified as a variant of unknown significance but suspicious for pathogenicity for CDH23-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Uncertain	0.13
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.0094	T;T;.;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.41	T;T;T;T
MetaSVM	Uncertain	0.40	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.84	D
Sift4G	Pathogenic	0.0	D;.;D;D
Polyphen		1.0	.;D;.;.
Vest4		0.83
MVP		0.89
MPC		0.18
ClinPred		0.12	T
GERP RS		5.8
Varity_R		0.37
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs111033536; hg19: chr10-73572583;