ClinVar Miner

Submissions for variant NM_022124.6(CDH23):c.4000C>T (p.Arg1334Trp) (rs373276722)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel RCV001171524 SCV001334309 uncertain significance Usher syndrome 2020-05-26 reviewed by expert panel curation The allele frequency of the c.4000C>T (p.Arg1334Trp) variant in CDH23 is 0.0142% (5/35134) of Latino alleles by gnomAD v2.1.1 and the filtering allele frequency (95% CI) is 0.068% (15/13658), which is a low enough frequency to award PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss. This variant has been reported in 2 probands with nonsyndromic hearing loss, however, the evidence did not support a causative role for the variant. The variant was also identified in a proband presenting with a range of cardiac and developmental clinical features; however the variant was absent in an affected parent. (PM3 not met; SCV000297305.2, SCV000205132.4), and these clinical features are not associated with CDH23. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM2_Supporting.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000155442 SCV000205132 uncertain significance not specified 2019-11-18 criteria provided, single submitter clinical testing The p.Arg1334Trp variant in CDH23 has been previously reported in one individuals with hearing loss by our laboratory who harbored two additional variants in CDH23, though they were not phased. The p.Arg1334Trp variant has been identified in 0.004% (13/278312) of the total chromosomes by gnomAD. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: None.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000155442 SCV000297305 uncertain significance not specified 2015-10-31 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764917 SCV000896080 uncertain significance Deafness, autosomal recessive 12; Usher syndrome type 1D; Pituitary adenoma 5, multiple types 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV001239311 SCV001412180 uncertain significance not provided 2019-12-06 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 1334 of the CDH23 protein (p.Arg1334Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs373276722, ExAC 0.04%). This variant has not been reported in the literature in individuals with CDH23-related conditions. ClinVar contains an entry for this variant (Variation ID: 178685). 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.

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