Variant: NM_022124.6(CDH23):c.478G>A (p.Asp160Asn)

CA16044278

375463 (ClinVar)

Gene: CDH23

Condition: nonsyndromic genetic deafness

Inheritance Mode: Autosomal recessive inheritance

UUID: c72b6207-d300-43a0-8e56-44bb59445149

HGVS expressions

NM_022124.6:c.478G>A
NM_022124.6(CDH23):c.478G>A (p.Asp160Asn)
NC_000010.11:g.71566790G>A
CM000672.2:g.71566790G>A
NC_000010.10:g.73326547G>A
CM000672.1:g.73326547G>A
NC_000010.9:g.72996553G>A
NG_008835.1:g.174844G>A
ENST00000224721.12:c.478G>A
ENST00000398809.9:c.478G>A
ENST00000442677.4:n.478G>A
ENST00000643732.1:n.254G>A
ENST00000646131.1:n.142G>A
ENST00000224721.10:c.493G>A
ENST00000299366.11:c.478G>A
ENST00000398809.8:c.478G>A
ENST00000398842.7:c.301G>A
ENST00000461841.7:c.478G>A
ENST00000616684.4:c.478G>A
ENST00000622827.4:c.478G>A
NM_001171930.1:c.478G>A
NM_001171931.1:c.478G>A
NM_001171932.1:c.478G>A
NM_022124.5:c.478G>A
NM_052836.3:c.478G>A
NM_001171930.2:c.478G>A
NM_001171931.2:c.478G>A
NM_052836.4:c.478G>A
NM_001171932.2:c.478G>A

Uncertain Significance

• Met criteria codes: PM2_Supporting PP4 PP3 PM3

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

Evidence submitted by expert panel

Hearing Loss VCEP

The NM_022124.6:c.478G>A variant in the CDH23 gene is a missense variant predicted to cause substitution of aspartic acid to asparagine at amino acid 160 (p.Asp160Asn). The computational predictor REVEL gives a score of 0.8, evidence that correlates with impact to CDH23 function (PP3). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0008% (1/112644 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.007%) for PM2_Supporting. This variant has been identified in one individual homozygous for the variant with Usher syndrome (PMID: 2746042, 0.5 PM3 points, PP4). Another individual with hearing loss and cochlear implants at age 1 year harbored this variant and another pathogenic variant, though phase was unknown (PMID: 35020051, 0.5 PM3 points). A third individual with Usher syndrome had a variant of uncertain significance phase unknown (Invitae internal data, SCV001516999.2, 0 PM3 points). It has been reported in additional individuals with hearing loss who either did not have an age of onset noted or did not have a second variant reported (PMID: 35020051, 22899989). In summary, due to limited evidence, this variant is classified as a variant of uncertain significance based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss Variant Curation Expert Panel: PM2_supporting, PM3, PP3, PP4. (VCEP specifications version 2.0.0; Dec 21, 2022)

Met criteria codes

• PM2_Supporting: The highest population minor allele frequency in gnomAD v2.1.1 is 0.0008% (1/112644 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.007%) for PM2_Supporting.
• PP4: Observed in Usher syndrome patients, see PM3
• PP3: Revel score of 0.805, meets threshold for PP3
• PM3: This variant has been identified in one individual homozygous for the variant with Usher syndrome (PMID: 2746042, 0.5 PM3 points, PP4). Another individual with hearing loss and cochlear implants at age 1 year harbored this variant and another pathogenic variant, though phase was unknown (PMID: 35020051, 0.5 PM3 points). A third individual with Usher syndrome had a variant of uncertain significance phase unknown (Invitae internal data, SCV001516999.2, 0 PM3 points). It has been reported in additional individuals with hearing loss who either did not have an age of onset noted or did not have a second variant reported (PMID: 35020051, 22899989).

Approved on: 2022-12-21

Published on: 2023-02-06