ClinVar Miner

Submissions for variant NM_022124.6(CDH23):c.5712G>A (p.Thr1904=)

gnomAD frequency: 0.00001  dbSNP: rs397517342
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000039224 SCV000062908 pathogenic Rare genetic deafness 2011-10-10 no assertion criteria provided clinical testing The Thr1904Thr variant in CDH23 has been reported in 2 individuals with Usher sy ndrome and was absent from 200 control chromosomes (von Brederlow 2002, Vozzi 20 11). This variant was identified to be in trans with another CDH23 variant in on e individual and homozygous in the other individual with Usher syndrome. In addi tion, the Thr1904Thr variant occurs as the last base of an exon which is part of the splicing consensus sequence. Exon-trapping assays reveal that the variant c auses skipping of exon 43 that does not disrupt the reading frame but is predict ed to lead to a 44 amino acid deletion (von Brederlow, 2002). In summary, this e vidence meets our criteria for this variant to be classified as pathogenic.
Natera, Inc. RCV001826574 SCV002092499 pathogenic Usher syndrome type 1 2021-01-22 no assertion criteria provided clinical testing

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