Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Link to SEPIO compliant JSON-LD document

Variant: NM_022124.6(CDH23):c.1515-12G>A

CA5543878

228484 (ClinVar)

Gene: CDH23

Condition: Usher syndrome

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 5f971d36-d0a1-4497-8de3-e5518d6d9d9b

HGVS expressions

NM_022124.6:c.1515-12G>A

NM_022124.6(CDH23):c.1515-12G>A

NM_001171930.1:c.1515-12G>A

NM_001171931.1:c.1515-12G>A

NM_022124.5:c.1515-12G>A

ENST00000224721.10:c.1530-12G>A

ENST00000299366.11:c.1515-12G>A

ENST00000398809.8:c.1515-12G>A

ENST00000442677.3:n.290-12G>A

ENST00000466757.7:n.946-12G>A

ENST00000616684.4:c.1515-12G>A

ENST00000622827.4:c.1515-12G>A

NC_000010.11:g.71677444G>A

CM000672.2:g.71677444G>A

NC_000010.10:g.73437201G>A

CM000672.1:g.73437201G>A

NC_000010.9:g.73107207G>A

NG_008835.1:g.285498G>A

Uncertain Significance

PM3 PM2_Supporting PP3

Evidence Links 0

Expert Panel

Hearing Loss VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Hearing Loss VCEP

The allele frequency of the c.1515-12G>A variant in the CDH23 gene is 0.01% (1/9692) of Ashkenazi Jewish chromosomes by gnomAD, which is a low enough frequency to apply PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_Supporting). Computational prediction tools and conservation analysis suggest that the c.1515-12G>A variant may impact splicing (PP3). This variant was reported in two patients with Usher syndrome (GeneDx unpublished data SCV000564845.2, Human Genetics Radboudumc unpublished data SCV000804605.2) and one with sloping sensorineural hearing loss (LMM unpublished data SCV000271550.2). The probands with Usher syndrome had a suspected-pathogenic variant in CDH23 with an unknown phase (PM3; SCV000564845.2, SCV000804605.2). In summary, the clinical significance of this variant is uncertain based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel (PM2_Supporting, PM3, PP3).

PM3

GeneDX reported finding this variant in combination with another CDH23 variant c.5188-1G>A in a patient that was sequenced in an Usher syndrome panel. This c.5188-1G>A is absent from v2.1.1 of gnomAD and present in 0.045% (1/2154) of "other" chromosomes in gnomAD v3. It is absent from ClinVar. This was given 0.5 points for a suspected pathogenic variant in trans. Human Genetics Radboudumc found this variant in combination with the CDH23 variant c.3248dup (p.His1143GlnfsTer3). This was scored 0.5 points due to the presence of a suspected pathogenic variant. A female individual with sloping sensorineural hearing loss with family history was found to harbor this variant and the p.Arg3138Gln variant in CDH23. The p.Arg3138Gln variant has only been reported once in ClinVar (this proband) with the VUS classification. The frequency for the variant in gnomAD is 0.00049. This proband was not scored any PM3 point. Total of 1 point for PM3 leads to a PM3 classification according to the HL VCEP guidelines.

PM2_Supporting

The variant is present in 0.01% (1/9692) of Ashkenazi Jewish chromosomes in gnomAD v2.1.1. The variant is present in 0.007% (3/41980) of African chromosomes in gnomAD v3.

PP3

Multiple splicing predictors predict this variant leads to the creation of an intronic 3' splice site (AG site) that would cause a frameshift. The nucleotide is not highly conserved but no other vertebrate in the UCSC database has a G at this position.

Approved on: 2019-11-26

Published on: 2019-11-26

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