CDH23 T1209A - GET-Evidence

Note: This variant has not been sufficiently evaluated by a GET-Evidence editor.

To be considered sufficiently evaluated a variant must have both "variant evidence" and "clinical importance" scores filled in.

Please help improve GET-Evidence by evaluating evidence for this variant!

Curation:
Currentness:

CDH23 T1209A

(CDH23 Thr1209Ala)


Short summary

This variant has been found in three individuals with Usher Syndrome (two homozygous), and is included in diagnostic tests for the disease. The variant frequency is high, however, in the African population.

Usher syndrome is also known as Hallgren syndrome, Usher-Hallgren syndrome, rp-dysacusis syndrome, and dystrophia retinae dysacusis syndrome. People with Usher syndrome show deafness due to a defective inner ear and gradual blindness associated with retinal degeneration.

Variant evidence
Computational 3

Gene Tests, functionally important, conserved residue, in-silico data predicts aberrant splicing
PolyPhen: Probably damaging 0.984
SIFT: Tolerated 0.14
GVGD: GV 0.00; GD 58.02; Class C55
Mutation Tasting Prediction: Disease causing, P value: 960992; protein features (might be) affected (aa 1103-1208 DOMAIN Cadherin 11 might get lost (downstream of altered splice site)
Variant Effect Predictor (Ensembl):
SIFT=tolerated(0.12);
PolyPhen=probably_damaging(0.984);
Condel=deleterious(0.942)

See Zheng QY et al. 2005 (15537665), Becirovic E et al. 2008 (18273900), unpublished research (below).

Functional -1

A mini-gene assay showed no aberrant splicing

See Becirovic E et al. 2008 (18273900).

Case/Control -1

OR=2.755, p-value=0.18. The high incidence of this variant in African & African American genomes and the observation of this variant homozygously in a apparently healthy individual contradicts the published hypothesis of this variant as being significantly pathogenic and fully penetrant.

See Astuto LM et al. 2002 (12075507), Zheng QY et al. 2005 (15537665), unpublished research (below).

Familial -
 
Clinical importance
Severity 4

congenital profound hearing loss, vestibular areflexia and adolescent-onset retinitis pigmentosa.

See unpublished research (below).

Treatability 4

cochlear implants recommended, routine ophthalmic evaluations and additional care to prevent injury due to impaired balance

Penetrance -
 

Impact

Insufficiently evaluated pathogenic

(The "insufficiently evaluated" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern

recessive

Summary of published research, and additional commentary

This is one of the 58 mutations in CDH23 included in the Gendia Usher Microarray (http://www.gendia.net/t18_note7.html)

Total cases/controls case+ case– control+ control– p-value odds ratio
Usher Syndrome Type 1
2 143 0 196 0.1801

 

Allele frequency

  • None available.

Publications
 

Astuto LM, Bork JM, Weston MD, Askew JW, Fields RR, Orten DJ, Ohliger SJ, Riazuddin S, Morell RJ, Khan S, Riazuddin S, Kremer H, van Hauwe P, Moller CG, Cremers CW, Ayuso C, Heckenlively JR, Rohrschneider K, Spandau U, Greenberg J, Ramesar R, Reardon W, Bitoun P, Millan J, Legge R, Friedman TB, Kimberling WJ. CDH23 mutation and phenotype heterogeneity: a profile of 107 diverse families with Usher syndrome and nonsyndromic deafness. Am J Hum Genet. 2002 Aug;71(2):262-75. Epub 2002 Jun 19. PubMed PMID: 12075507; PubMed Central PMCID: PMC379159.

In a screen of CDH23 in 107 individuals with Usher Syndrome (69) or non-syndromic deafness (38) this variant was found homozygously in one individual with Usher Syndrome. The authors note that Usher Syndrome is usually caused by a null allele, and the presentation of this case was “atypical.” Ancestry is not reported and “adequate clinical information could not be obtained.” Additionally, the authors did not directly sequence all 69 exons for each individual. This variant was not seen in 96 control samples.

Cases/controls case+ case– control+ control– p-value odds ratio
Usher Syndrome Type 1
1 68 0 96 0.4182

 

Zheng QY, Yan D, Ouyang XM, Du LL, Yu H, Chang B, Johnson KR, Liu XZ. Digenic inheritance of deafness caused by mutations in genes encoding cadherin 23 and protocadherin 15 in mice and humans. Hum Mol Genet. 2005 Jan 1;14(1):103-11. Epub 2004 Nov 10. PubMed PMID: 15537665; PubMed Central PMCID: PMC2858222.

In a study of 76 probands assessing digenic inheritance of Usher Syndrome between CDH23 and PCDH15, this variant was found in a homozygous state together with 5601delAAC in PCDH15. This patient was a 43yo African-American female with congenital deafness, balance problems at 29yo, retinitis pigmentosa at 30yo and night blindness at 40yo. The authors note that this phenotype is more severe than that of Astuto et al., possibly due to a modifier effect from PCDH15. This variant is in a functionally important, conserved domain and was not seen in 100 unrelated controls.

Cases/controls case+ case– control+ control– p-value odds ratio
Usher Syndrome Type 1
1 75 0 100 0.4318

 

Cremers FP, Kimberling WJ, Külm M, de Brouwer AP, van Wijk E, te Brinke H, Cremers CW, Hoefsloot LH, Banfi S, Simonelli F, Fleischhauer JC, Berger W, Kelley PM, Haralambous E, Bitner-Glindzicz M, Webster AR, Saihan Z, De Baere E, Leroy BP, Silvestri G, McKay GJ, Koenekoop RK, Millan JM, Rosenberg T, Joensuu T, Sankila EM, Weil D, Weston MD, Wissinger B, Kremer H. Development of a genotyping microarray for Usher syndrome. J Med Genet. 2007 Feb;44(2):153-60. Epub 2006 Sep 8. PubMed PMID: 16963483.

In developing a microarray for Usher Syndrome, testing of 370 Caucasian cases (140 with Usher Syndrome I) this variant was found heterozygously in 1/20 individuals with Atypical Usher Syndrome.

Becirovic E, Ebermann I, Nagy D, Zrenner E, Seeliger MW, Bolz HJ. Usher syndrome type 1 due to missense mutations on both CDH23 alleles: investigation of mRNA splicing. Hum Mutat. 2008 Mar;29(3):452. PubMed PMID: 18273900.

In silico data suggest that this variant causes aberrant splicing (assessed with ESE finder) and would explain why it is one of only four CDH23 missense mutations causing Usher Syndrome. This variant is conserved in mouse, chicken and zebrafish. A mini-gene assay showed no difference in splicing when compared with wildtype. The authors conclude that due to the work of Astuto and Zheng pathogenicity is likely, but it is still possible that additional mutations were missed.

Genomes
 

hu728FFF - PGP11 (hu728FFF) build 36, substitution variants
het G @ chr10:73160277

 

NA19240

 

show discussion

Discussion

This area of Na19240’s genome has been re-sequenced and the variant has been confirmed to be a heterozygous G.

Other external references
 

    GeneTests
  • GeneTests records for the CDH23 gene
    Nonsyndromic Hearing Loss and Deafness, Autosomal Recessive
    Usher Syndrome Type 1
    DFNB12 Nonsyndromic Hearing Loss and Deafness
    Usher Syndrome Type 1D
    www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/CDH23

Other in silico analyses
 

  • NBLOSUM100 score = 1
  • GET-Evidence autoscore = 5

Edit history
 

Gene search

"GENE" or "GENE A123C":

Log in