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]

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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

Approved on: 2023-10-18

Published on: 2024-07-02

HGVS expressions

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

NM_022124.6(CDH23):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

ENST00000224721.12:c.1515-12G>A

ENST00000398809.9:c.1515-12G>A

ENST00000442677.4:c.1515-12G>A

ENST00000466757.8:c.946-12G>A

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

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

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

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

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

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

ENST00000622827.4: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

NM_001171930.2:c.1515-12G>A

NM_001171931.2:c.1515-12G>A

Uncertain Significance

PP4 PP3 PM3

PM2

Evidence Links 0

Expert Panel

Hearing Loss VCEP

Criteria Specification Information

Criteria Specification: ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CDH23, COCH, GJB2, KCNQ4, MYO6, MYO7A, SLC26A4, TECTA and USH2A Version 2

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Hearing Loss VCEP

The c.1515-12G>A variant in CDH23 is an intronic variant which is located in intron 15. The highest population minor allele frequency in gnomAD v2.1.1 is 0.009% ( 2/21986) in the African/African American population (PM2_supporting, BS1, and BA1 not met). The results from 3 in silico splicing predictors including MaxEntScan indicate that this variant may affect splicing by disrupting the acceptor splice site (PP3). This variant has been detected in 3 individuals with hearing loss and 2 individuals with Usher syndrome. The individuals with Usher syndrome were compound heterozygous for the variant and a pathogenic or likely pathogenic variant; however, phase was not confirmed in trans (PM3, PP4, SCV000564845.4, SCV000804605.2). In summary, this variant is classified as uncertain significance based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PP3, PM3, PP4 (ClinGen Hearing Loss VCEP specifications version 2; 10.18.2023).

PP4

This variant has been detected in 3 individuals with hearing loss and 2 individuals with Usher syndrome. The individuals with Usher syndrome were compound heterozygous for the variant and a pathogenic or likely pathogenic variant; however, phase was not confirmed in trans (PM3, PP4, SCV000564845.4, SCV000804605.2).

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.

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

The highest population minor allele frequency in gnomAD v2.1.1 is 0.009% ( 2/21986) in the African/African American population (PM2_supporting, BS1, and BA1 not met).

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