Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000039224 | SCV000062908 | likely pathogenic | Rare genetic deafness | 2024-02-01 | criteria provided, single submitter | clinical testing | The c.5712G>A (p.Thr1904Thr) variant in CDH23 has been identified in 4 individuals with Usher syndrome (1 homozygote and 3 compound heterozygotes with another disease causing variant in CDH23) and segregated with disease in 2 affected relatives from 2 families (von Brederlow 2002 PMID: 11857743, Vozzi 2011 PMID: 21738395, LMM internal data). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 45989) and has been identified in 0.002% (1/41468) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). This variant is located in the last base of the exon, which is part of the 5’ splice region. Computational tools predict a splicing impact and exon-trapping assays reveal that the variant causes skipping of exon 43 which does not result in the disruption of the reading frame (von Brederlow 2002 PMID: 11857743). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Usher syndrome. ACMG/AMP Criteria applied: PM3_Strong, PS3_Moderate, PP1_Moderate, PM2_Supporting. |
| Invitae | RCV001852822 | SCV002241130 | pathogenic | not provided | 2023-07-28 | criteria provided, single submitter | clinical testing | This variant has been observed in individual(s) with Usher syndrome (PMID: 11857743, 21738395). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 42, but is expected to preserve the integrity of the reading-frame (PMID: 11857743). ClinVar contains an entry for this variant (Variation ID: 45989). This variant is present in population databases (rs397517342, gnomAD 0.007%). This sequence change affects codon 1904 of the CDH23 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the CDH23 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. |
| Baylor Genetics | RCV003473279 | SCV004210630 | likely pathogenic | Pituitary adenoma 5, multiple types | 2023-08-23 | criteria provided, single submitter | clinical testing | |
| Prevention |
RCV004534833 | SCV004739382 | pathogenic | CDH23-related disorder | 2024-02-15 | criteria provided, single submitter | clinical testing | The CDH23 c.5712G>A variant is not predicted to result in an amino acid change (p.=). This variant occurs at the last nucleotide of exon 43 and is predicted to impact splicing (Alamut Visual Plus v1.6.1). This variant was reported in the homozygous or compound heterozygous state in individuals with Usher syndrome or inherited retinal disease (von Brederlow et al. 2002. PubMed ID: 11857743; Vozzi et al. 2011. PubMed ID: 21738395; Supplemental Table, Holtan et al. 2019. PubMed ID: 31429209; Table S1, Karali et al. 2022. PubMed ID: 36460718). In vitro exon skipping experiments showed that the c.5712G>A variant results in skipping of exon 43, which does not alter the reading frame but would result in the loss of 70 amino acids (von Brederlow et al. 2002. PubMed ID: 11857743). This variant is reported in 0.0065% of alleles in individuals of African descent in gnomAD. This variant is interpreted as pathogenic. |
| Natera, |
RCV001826574 | SCV002092499 | pathogenic | Usher syndrome type 1 | 2021-01-22 | no assertion criteria provided | clinical testing |