ClinVar Miner

Submissions for variant NM_022124.6(CDH23):c.6091G>A (p.Ala2031Thr)

gnomAD frequency: 0.00004  dbSNP: rs368381520
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Total submissions: 5
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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 RCV000150306 SCV000197381 uncertain significance not specified 2018-07-25 criteria provided, single submitter clinical testing The p.Ala2031Thr variant in CDH23 has been previously reported by our laboratory in one individual with severe sensorineural hearing loss; however, the hearing loss was likely due to a homozygous pathogenic variant in a different gene in th is individual. It has been identified in 0.01% (15/110508) of European chromosom es by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs368381520). This variant has also been reported in ClinVar (Variation I D 162926). Computational prediction tools and conservation analysis suggest that the p.Ala2031Thr variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical signific ance of the p.Ala2031Thr variant is uncertain. ACMG/AMP Criteria applied: PP3, P M2_Supporting.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000150306 SCV000602957 uncertain significance not specified 2017-02-24 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001850039 SCV002294302 uncertain significance not provided 2024-09-15 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2031 of the CDH23 protein (p.Ala2031Thr). This variant is present in population databases (rs368381520, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with CDH23-related conditions. ClinVar contains an entry for this variant (Variation ID: 162926). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt CDH23 protein function with a negative predictive value of 95%. 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.
Ambry Genetics RCV003278670 SCV004005893 uncertain significance Inborn genetic diseases 2023-04-18 criteria provided, single submitter clinical testing The c.6091G>A (p.A2031T) alteration is located in exon 47 (coding exon 46) of the CDH23 gene. This alteration results from a G to A substitution at nucleotide position 6091, causing the alanine (A) at amino acid position 2031 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Natera, Inc. RCV001274899 SCV001459452 uncertain significance Usher syndrome type 1 2020-09-16 no assertion criteria provided clinical testing

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