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_022124.5(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: 2019-10-18
Published on: 2019-10-18

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:c.3498C>T
ENST00000647092.1:c.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
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Uncertain Significance

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

Evidence Links 3

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Hearing Loss VCEP
The c.9565C>T (p.Arg3189Trp) variant in CDH23 has been identified in 2 heterozygous patients with Usher syndrome without another CDH23 variant in trans (Partners LMM internal data, SCV000062996.5; PMID 22381527, 18395802). This 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_Supporting threshold (BS1/PM2 not met). The REVEL computational prediction analysis tool produced a score of 0.8, which is above the threshold necessary to apply PP3; however, this information is not predictive of pathogenicity on its own. A different missense variant (p.Arg3189Gln) has been previously identified at this codon of CDH23, however this variant does not have enough evidence to support pathogenicity (PM5 not met; ClinVar Variation ID 162956). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PP3.
Met criteria codes
PP3
REVEL score = 0.783
Not Met criteria codes
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP2
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.
PM1
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.
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
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
Patient No. 1 was found to carry the 16delT mutation in exon 2 of PCDH15 and p.Arg3189Trp CDH3 variant PubMed:18395802
PM5
NM_022124.5(CDH23):c.9566G>A (p.Arg3189Gln). ClinVar ID: 162956. Variant is VUS.
PM4
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.
PS1
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
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
BA1
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
BP4
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
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
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
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
Patient No. 1 was found to carry the 16delT mutation in exon 2 of PCDH15 and p.Arg3189Trp CDH3 variant PubMed:18395802
BS2
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.
BS4
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
Curation History
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