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.3625A>G (p.Thr1209Ala)

CA137387

4927 (ClinVar)

Gene: CDH23
Condition: Usher syndrome
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: dfd4f5fa-53f6-478c-911d-6946d1680d38
Approved on: 2019-05-28
Published on: 2019-07-17

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
More

Benign

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

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
BP4
Additionally, computational prediction analysis using the metapredictor tool REVEL suggests that the variant may not impact the protein (BP4).
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).
Using a minigene assay, this paper investigated 3 different CDH23 variants for their possible impact on mRNA splicing. They state that in silico analysis suggested the impairment of splicing, however splicing was normal for this variant. PubMed:18273900
Not Met criteria codes
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
BP2
Variant was identified in trans with the p.Ala366Thr variant in CDH23 in a patient with USH2. The p.Ala366Thr variant has been classified as Benign/LB by 5 labs in ClinVar on the basis of it being in 1% of the population. This paper also reports the heterozygote RP683 reported in Cremers et al who had undisclosed type of Usher syndrome. PubMed:19683999
Variant identified in a patient from USA of European ancestry who was homozygous for the variant. The patient had Usher syndrome PubMed:15660226
Variant identified in a proband in a family with recessive Usher syndrome type I in a homozygous state. No further information about the segregation status of this family. PubMed:12075507
Variant was identiefied in a homozygous state in family 1677. The proband was a 43 year old American female patient of African ancestry with Usher syndrome. USH may be due to modifier effect of PCDH15 5601delAAC. Indicated that the varint is pathogenic. PubMed:15537665
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
PVS1
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
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%.
Study perofremd a genotyping microarray for 298 Usher syndrome variants and validated them in 370 unrelated European and American patients with Usher syndrome. The variant was identiified in one individual in a heterozygous state. PubMed:16963483
This paper sequenced all the coding exons of the 9 USH genes in 54 patients and found the variant in the cohort. The zygosity of the variant is unclear but they state that it is a presumably neutral missense variant due to its presence in 5/486 contorl alleles from French and Maghreban populations. They do cite two other papers that have identified this variant as pathogenic. PubMed:21569298
Variant was identified in 2 heterozygotes with Usher syndrome after screening of 75 unrelated Italian patinets.One of the patients also carried a p.E767fs variant in USH2A in a het state. PubMed:21738395
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
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
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.
Variant was identified in trans with the p.Ala366Thr variant in CDH23 in a patient with USH2. The p.Ala366Thr variant has been classified as Benign/LB by 5 labs in ClinVar on the basis of it being in 1% of the population. This paper also reports the heterozygote RP683 reported in Cremers et al who had undisclosed type of Usher syndrome. PubMed:19683999
Variant identified in a patient from USA of European ancestry who was homozygous for the variant. The patient had Usher syndrome PubMed:15660226
Variant identified in a proband in a family with recessive Usher syndrome type I in a homozygous state. No further information about the segregation status of this family. PubMed:12075507
Variant was identiefied in a homozygous state in family 1677. The proband was a 43 year old American female patient of African ancestry with Usher syndrome. USH may be due to modifier effect of PCDH15 5601delAAC. Indicated that the varint is pathogenic. PubMed:15537665
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
PM2
Met BA1
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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