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]

Variant: NM_022124.5(CDH23):c.9565C>T (p.Arg3189Trp)

CA117145

4926 (ClinVar)

Gene: CDH23
Condition: Usher syndrome
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 4208d780-9d29-4b4a-877f-2c815a5dae87
Approved on: 2022-07-21
Published on: 2022-09-26

HGVS expressions

NM_022124.5:c.9565C>T
NM_022124.5(CDH23):c.9565C>T (p.Arg3189Trp)
NC_000010.11:g.71812822C>T
CM000672.2:g.71812822C>T
NC_000010.10:g.73572579C>T
CM000672.1:g.73572579C>T
NC_000010.9:g.73242585C>T
NG_008835.1:g.420876C>T
ENST00000224721.12:c.9565C>T
ENST00000642965.1:n.3498C>T
ENST00000647092.1:n.3162C>T
ENST00000224721.10:c.9580C>T
ENST00000398788.4:c.2845C>T
ENST00000475158.1:n.3101C>T
ENST00000619887.4:c.2845C>T
ENST00000622827.4:c.9565C>T
NM_001171933.1:c.2845C>T
NM_001171934.1:c.2845C>T
NM_001171935.1:c.256C>T
NM_001171936.1:c.256C>T
NM_022124.6:c.9565C>T
NM_022124.6(CDH23):c.9565C>T (p.Arg3189Trp)
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Uncertain Significance

Met criteria codes 1
PP3
Not Met criteria codes 25
PS3 PS4 PS2 PS1 PP1 PP4 PP2 PM6 PM2 PM4 PM3 PM1 PM5 BA1 BS3 BS4 BS1 BS2 PVS1 BP5 BP7 BP3 BP2 BP4 BP1

Evidence Links 3

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.9565C>T variant in CDH23 is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 3189. The only evidence resulting in a classification code was determined by the computational predictor REVEL which gives a score of 0.783, which is above the threshold of 0.7, evidence that correlates with impact to CDH23 function (PP3). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00039 (4/10320 alleles) in the Ashkenazi Jewish population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PP3 (ClinGen Hearing Loss VCEP specifications version 2; 6/15/2022).
Met criteria codes
PP3
The computational predictor REVEL which gives a score of 0.783, which is above the threshold of 0.7, evidence that correlates with impact to CDH23 function (PP3).
Not Met criteria codes
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP4
If identified in an USH1 patient would meet PP4. Can't be used because none of the patients presented had biallelic variants.
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM2
Variant was identified in 4/10120 (0.00040) Ashkenazi Jewish alleles in gnomAD. This is above the BS1 autosomal recessive threshold of 0.02% of alleles.
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM3
The only patients that have been reported are heterozygotes. There is one patient with a frameshift in PCDH15 and the argument has been made for digenic inheritance, however this is not evidence to be counted for PM3.
In family 239, the deaf proband was heterozygous for a 16delT mutation in exon 2 of PCDH15 and for a C!T transition at nucleotide 9565 of codon 3189 (R3189W) of CDH23 (data not shown). The normal hearing brother of the patient was found to be heterozygous only for the 16delT mutation in PCDH15. This is likely the same proband as the Liu report because of author overlap. PubMed:22381527
Variant was identified as a novel variant in a heterozygous occurrence in a patient from the USA of European ancestry with USH1. No other variant identified. PubMed:15660226
Patient No. 1 was found to carry the 16delT mutation in exon 2 of PCDH15 and p.Arg3189Trp CDH3 variant PubMed:18395802
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
NM_022124.5(CDH23):c.9566G>A (p.Arg3189Gln). ClinVar ID: 162956. Variant is VUS.
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
Variant was identified in 4/10120 (0.00040) Ashkenazi Jewish alleles in gnomAD. This is above the BS1 autosomal recessive threshold of 0.02% of alleles. However the filtering allele frequency of the variant is 0.00003979. Which is less than the BS1 threshold.
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
In family 239, the deaf proband was heterozygous for a 16delT mutation in exon 2 of PCDH15 and for a C!T transition at nucleotide 9565 of codon 3189 (R3189W) of CDH23 (data not shown). The normal hearing brother of the patient was found to be heterozygous only for the 16delT mutation in PCDH15. This is likely the same proband as the Liu report because of author overlap. PubMed:22381527
Variant was identified as a novel variant in a heterozygous occurrence in a patient from the USA of European ancestry with USH1. No other variant identified. PubMed:15660226
Patient No. 1 was found to carry the 16delT mutation in exon 2 of PCDH15 and p.Arg3189Trp CDH3 variant PubMed:18395802
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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