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.3625A>G (p.Thr1209Ala)

CA137387

4927 (ClinVar)

Gene: CDH23
Condition: Usher syndrome
Inheritance Mode: Autosomal recessive inheritance
UUID: dfd4f5fa-53f6-478c-911d-6946d1680d38

HGVS expressions

NM_022124.5:c.3625A>G
NM_022124.5(CDH23):c.3625A>G (p.Thr1209Ala)
NC_000010.11:g.71730514A>G
CM000672.2:g.71730514A>G
NC_000010.10:g.73490271A>G
CM000672.1:g.73490271A>G
NC_000010.9:g.73160277A>G
NG_008835.1:g.338568A>G
NM_001168390.1:c.-6+7214T>C
NM_001171930.1:c.3625A>G
ENST00000224721.10:c.3640A>G
ENST00000398786.2:c.-6+7214T>C
ENST00000398792.3:n.317A>G
ENST00000398809.8:c.3622A>G
ENST00000616684.4:c.3625A>G
ENST00000622827.4:c.3625A>G

Benign

Met criteria codes 3
BA1 BS3_Supporting BP4
Not Met criteria codes 21
BP2 BP3 BP5 BP7 BS2 BS1 BS4 PVS1 PP3 PP1 PP4 PS3 PS4 PS1 PS2 PM2 PM6 PM3 PM4 PM5 PM1

Evidence Links 8

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Hearing Loss VCEP
The filtering allele frequency (the lower threshold of the 95% CI of 3442/23972) of the c.3625A>G (p.Thr1209Ala) variant in the CDH23 gene is 13.15% for African chromosomes by gnomAD, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). A splicing assay did not show any impact to splicing but BS3 was not applied given no assessment of protein function (PMID:18273900). Computational prediction analysis using the metapredictor tool REVEL did not predict an impact the protein (BP4). Of note, this variant was reported in 3 patients with Usher syndrome (PMID: 15537665, 15660226, 12075507) though without any convincing evidence for pathogenicity (PM3 not met). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel : BA1, BS3_Supporting, BP4.
Met criteria codes
BA1
The filtering allele frequency of the c.3625A>G (p.Thr1209Ala) variant in the CDH23 gene is 13.15% for African chromosomes by gnomAD (3442/23972 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1).
BS3_Supporting
Minigene assay indicates that this variant does not impact splicing Becirovic 2008, PMID18273900. A functional study demonstrates that this variant may not impact protein function (BS3_Supporting; PMID:18273900).

BP4
Additionally, computational prediction analysis using the metapredictor tool REVEL suggests that the variant may not impact the protein (BP4).
Not Met criteria codes
BP2
BP3
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
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
Met BA1
BS4
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
PP3
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
None of patients reported were specifically described to have Usher syndrome I
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
There are 4 heterozygotes and 4 homozygotes reported in literature. The highest subpopulation in gnomAD was 14% in African alleles. The highest frequency of this variant in any affected cohort was the 2 heterozygotes in 75 Italian patients which is only 2.6%.

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
PM2
Met BA1
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM3
This variant meets the BA1 cutoff as it has been identified in 14% of African alleles in gnomAD. The variant has been reported in a total of 3 homozygous probands reported in the literature PMID: 15537665, 15660226, 12075507 as well as a compound heterozygous variant p.Ala366Thr that meets BA1 PMID: 19683999. Consanguinity of all families was not reported. Using the new PM3 proposal, this variant does not meet PM3 (as the homozygous occurrences award the variant 1 point but meeting BA1 subtracts 4 pts). Using the original PM3 rules, the variant meets PM3 due to the 3 homozygous occurrences. Note: Roberts et al. 2017 not in PubMed had case of South African Populations with inherited retinal disease in a homozygous state.

PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Approved on: 2019-05-28
Published on: 2019-07-17
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