ClinVar Miner

Submissions for variant NM_022124.6(CDH23):c.7361C>T (p.Thr2454Met)

gnomAD frequency: 0.00009  dbSNP: rs772949926
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV001195486 SCV001365863 uncertain significance not specified 2019-05-22 criteria provided, single submitter clinical testing The p.Thr2454Met variant in CDH23 has been previously identified in 1 patient with hearing loss who harbored another CDH23 variant in trans (Jung 2017). The p.Thr2454Met variant has been identified in 0.03% (10/30602) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied: PM2_Supporting, PP3, PM3_Supporting.
Labcorp Genetics (formerly Invitae), Labcorp RCV001243656 SCV001416828 uncertain significance not provided 2022-08-16 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 2454 of the CDH23 protein (p.Thr2454Met). This variant is present in population databases (rs772949926, gnomAD 0.03%). This missense change has been observed in individual(s) with congenital deafness (PMID: 28383030, 32467589). ClinVar contains an entry for this variant (Variation ID: 930067). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C65"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV001243656 SCV005384467 uncertain significance not provided 2024-04-25 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in patients with sensorineural hearing loss in published literature (PMID: 32467589, 28383030); This variant is associated with the following publications: (PMID: 34426522, 32467589, 28383030)
Natera, Inc. RCV001833762 SCV002093344 uncertain significance Usher syndrome type 1 2020-01-21 no assertion criteria provided clinical testing

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