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]

Variant: NM_022124.5(CDH23):c.2866G>A (p.Glu956Lys)

Curation Version - 1.1
Curation History
JSON LD for Version 1.1

CA5544361

444219 (ClinVar)

Gene: CDH23

Condition: sensorineural hearing loss disorder

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: ad55f8aa-c75a-44f6-9a6e-2344d0525a05

Approved on: 2020-11-02

Published on: 2020-11-02

HGVS expressions

NM_022124.5:c.2866G>A

NM_022124.5(CDH23):c.2866G>A (p.Glu956Lys)

NC_000010.11:g.71705043G>A

CM000672.2:g.71705043G>A

NC_000010.10:g.73464800G>A

CM000672.1:g.73464800G>A

NC_000010.9:g.73134806G>A

NG_008835.1:g.313097G>A

ENST00000224721.12:c.2866G>A

ENST00000398809.9:c.2866G>A

ENST00000442677.4:c.2866G>A

ENST00000466757.8:c.2297G>A

ENST00000224721.10:c.2881G>A

ENST00000299366.11:c.2866G>A

ENST00000398809.8:c.2866G>A

ENST00000442677.3:c.1641G>A

ENST00000466757.7:c.2297G>A

ENST00000616684.4:c.2866G>A

ENST00000622827.4:c.2866G>A

NM_001171930.1:c.2866G>A

NM_001171931.1:c.2866G>A

NM_001171930.2:c.2866G>A

NM_001171931.2:c.2866G>A

NM_022124.6:c.2866G>A

Likely Pathogenic

PM2_Supporting PP3 PM3_Strong

BP4

Evidence Links 3

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.2866G>A (p.Glu956Lys) variant in the CDH23 gene is 0.018% (13/42034) of African chromosomes by gnomAD v3, 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). This variant has been reported in five probands with hearing loss without evidence of retinal disease (PMID 25963016, 22899989). Four of these individuals also harbored the p.Pro240Leu pathogenic variant in CDH23; however, only three were confirmed in trans (PM3_Strong, PMID 25963016, 22899989). The fifth individual also harbored the p.Asp645Gly variant in CDH23, but phasing was not performed (PMID 25963016). The REVEL computational prediction analysis tool produced a score of 0.616, which was just below the threshold to automatically apply PP3, but the Expert Panel decided to apply PP3 based upon manual review of alignments to examine conservation. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PM3_Strong, PM2_Supporting, PP3.

PM2_Supporting

Updated: 0.018% (13/42034) of African chromosomes by gnomADv3. Absent from gnomAD v2.1.1

PP3

The REVEL computational prediction analysis tool produced a score of 0.616, which was just below the threshold to automatically apply PP3, but the Expert Panel decided to apply PP3 based upon manual review of alignments to examine homology.

PM3_Strong

Variants weren’t confirmed to be in trans in Mizutari 2015, so scored PM3 (moderate), counting 0.5 points for the three p.P240L / p.E956K compound het probands.

Proband with congenital profound progressive SNHL who was cmp het with c.719C4T (p.P240L), phasing not performed PubMed:26763877

Four probands (likely one from Miyagawa 2012) who were compound het for E956K. Case 12 (11y2m) with normal vision/motor milestones - p.D645G / p.E956K. Case 13 9y7m with myopia and normal fundus exam, normal motor milestones- p.P240L / p.E956K. Case 15 8y5m with normal vision/motor milestones - p.P240L / p.E956K. Case 16 7y3m with normal vision/motor milestones - p.P240L / p.E956K. PubMed:25963016

Sample #462 had profound SNHL, patient was 10 years at age of awareness (assuming this means diagnosis?), and also harbored Pro240Leu, which was identified hom or comp het in over 10 probands. 2 probands were het only for Glu956Lys. Phasing not performed, PM3_Supporting. PubMed:22899989

BP4

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Curation History

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