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_022124.6(CDH23):c.9569C>T (p.Ala3190Val)

CA137643

46076 (ClinVar)

Gene: CDH23
Condition: Usher syndrome
Inheritance Mode: Autosomal recessive inheritance
UUID: 7f246a3f-3877-4e1c-b536-a8da21fcd3b6
Approved on: 2023-11-15
Published on: 2024-04-01

HGVS expressions

NM_022124.6:c.9569C>T
NM_022124.6(CDH23):c.9569C>T (p.Ala3190Val)
NC_000010.11:g.71812826C>T
CM000672.2:g.71812826C>T
NC_000010.10:g.73572583C>T
CM000672.1:g.73572583C>T
NC_000010.9:g.73242589C>T
NG_008835.1:g.420880C>T
ENST00000224721.12:c.9569C>T
ENST00000642965.1:c.3502C>T
ENST00000647092.1:c.3166C>T
ENST00000224721.10:c.9584C>T
ENST00000398788.4:c.2849C>T
ENST00000475158.1:n.3105C>T
ENST00000619887.4:c.2849C>T
ENST00000622827.4:c.9569C>T
NM_001171933.1:c.2849C>T
NM_001171934.1:c.2849C>T
NM_001171935.1:c.260C>T
NM_001171936.1:c.260C>T
NM_022124.5:c.9569C>T
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Uncertain Significance

Met criteria codes 2
BS2 PP3
Not Met criteria codes 4
BS1 PP4 PM2 PM3

Evidence Links 0

Expert Panel

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

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Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Hearing Loss VCEP
The c.9569C>T variant (NM_022124.6(CDH23):c.9569C>T (p.Ala3190Val)) in CDH23 is a missense variant predicted to cause substitution of alanine by valine at amino acid 3190 (p.Ala3190Val). The highest minor allele frequency in gnomAD v4.0.0 is 694/1179698 alleles (0.0005517), in the European (non-Finnish) population (no population codes met). This variant has been observed in a homozygous state in one parent reported to have no features of Usher syndrome (BS2; Invitae internal data; ClinVar SCV001110059.2). The computational predictor REVEL gives a score of 0.836, which is above the Hearing Loss VCEP threshold of 0.7, evidence that correlates with impact to CDH23 function (PP3). The variant was found in a compound heterozygous state with a deletion of exon 29, a variant which was not able to be confirmed by aCGH (PMID: 25404053). The variant was also found in an unknown phase with p.Arg3206Cys (c.9616C>T), a variant of uncertain significance, in an affected patient with nonsyndromic hearing loss (PMID: 27068579; PM3 not met). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss Expert Panel: BS2, PP3 (Version 2; 11/15/2023).
Met criteria codes
BS2
This variant has been observed in a homozygous state in one parent reported to have no features of Usher Syndrome (BS2; Invitae internal data; ClinVar SCV001110059.2).
PP3
The computational predictor REVEL gives a score of 0.836, which is above the Hearing Loss VCEP threshold of 0.7, evidence that correlates with impact to CDH23 function (PP3). Nucleotide is very well-conserved among 100 vertebrates in UCSC database. Variant is not predicted to impact splicing according to splice AI scores.
Not Met criteria codes
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM2
The highest major allele frequency in gnomAD v4.0.0 is is 694/1179698 (0.0005883) in the European (non-Finnish) population (no population codes met).
PM3
The variant was found in a compound heterozygous state with a deletion of exon 29, a variant which was not confirmed. The variant was also found in an unknown phase with p.Arg3206Cys (c.9616C>T), a variant of uncertain significance, in an affected patient with nonsyndromic hearing loss (PM3 not met).
Curation History
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