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

Variant: NM_022124.6(CDH23):c.4000C>T (p.Arg1334Trp)

CA182785

178685 (ClinVar)

Gene: CDH23
Condition: Usher syndrome
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: dd524d0a-42ad-482b-85f1-c9e3d378e600
Approved on: 2020-05-26
Published on: 2020-05-26

HGVS expressions

NM_022124.6:c.4000C>T
NM_022124.6(CDH23):c.4000C>T (p.Arg1334Trp)
NC_000010.11:g.71732271C>T
CM000672.2:g.71732271C>T
NC_000010.10:g.73492028C>T
CM000672.1:g.73492028C>T
NC_000010.9:g.73162034C>T
NG_008835.1:g.340325C>T
NM_001168390.1:c.-6+5457G>A
NM_001171930.1:c.4000C>T
NM_022124.5:c.4000C>T
NM_001168390.2:c.-6+5457G>A
NM_001171930.2:c.4000C>T
ENST00000224721.10:c.4015C>T
ENST00000398786.2:c.-6+5457G>A
ENST00000398792.3:n.692C>T
ENST00000398809.8:c.3997C>T
ENST00000616684.4:c.4000C>T
ENST00000622827.4:c.4000C>T
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Uncertain Significance

Met criteria codes 1
PM2_Supporting
Not Met criteria codes 5
BP2 BP4 PP4 PP3 PM3

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Hearing Loss VCEP
The allele frequency of the c.4000C>T (p.Arg1334Trp) variant in CDH23 is 0.0142% (5/35134) of Latino alleles by gnomAD v2.1.1 and the filtering allele frequency (95% CI) is 0.068% (15/13658), which is a low enough frequency to award PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss. This variant has been reported in 2 probands with nonsyndromic hearing loss, however, the evidence did not support a causative role for the variant. The variant was also identified in a proband presenting with a range of cardiac and developmental clinical features; however the variant was absent in an affected parent. (PM3 not met; SCV000297305.2, SCV000205132.4), and these clinical features are not associated with CDH23. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM2_Supporting.
Met criteria codes
PM2_Supporting
This variant is present in 0.0142% (5/35134) of Latino chromosomes in gnomAD v2.1.1. The filtering AF (95% CI) is 0.068% (15/13658) of Latino chromosomes in gnomAD v3.
Not Met criteria codes
BP2
Phasing was not performed on individuals from LMM, so it unclear if the variant was observed in cis.
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP4
There was no mention of retinitis pigmentosa or vestibular dysfunction in the LMM probands.
PP3
The REVEL score is 0.316. No splicing impact is predicted by the splicing predictors in Alamut including MaxEntScan. The R1334 residue is conserved across all mammals except the naked mole rat which has a Q (Gln) at this position.
PM3
Phasing of the variants is unclear for both LMM probands.
Curation History
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