ClinVar Miner

Submissions for variant NM_001146079.2(CLDN14):c.185A>G (p.Tyr62Cys)

gnomAD frequency: 0.00048  dbSNP: rs148223897
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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 RCV000219015 SCV000271585 uncertain significance not specified 2017-03-28 criteria provided, single submitter clinical testing The p.Tyr62Cys variant in CLDN14 has been previously detected by our laboratory in one individual with hearing loss who was heterozygous for the variant and did not carry a second CLDN14 variant. This variant has also been identified in 0.1 % (48/64036) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs148223897); however it's frequency is no t high enough to rule out a pathogenic role. Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though t his information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Tyr62Cys variant is uncertain.
GeneDx RCV001594877 SCV001827968 likely benign not provided 2019-12-31 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001594877 SCV002109446 uncertain significance not provided 2025-01-13 criteria provided, single submitter clinical testing This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 62 of the CLDN14 protein (p.Tyr62Cys). This variant is present in population databases (rs148223897, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with CLDN14-related conditions. ClinVar contains an entry for this variant (Variation ID: 228518). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
Clinical Genomics Laboratory, Washington University in St. Louis RCV003458356 SCV004177062 uncertain significance Vein of Galen aneurysmal malformation 2023-09-29 criteria provided, single submitter clinical testing The CLDN14 c.185A>G (p.Tyr62Cys) variant was identified at a near heterozygous allelic fraction. This variant, to our knowledge, has not been reported in the literature in association with lipomatous neoplasms. This variant has been reported in the ClinVar database as a variant of uncertain significance by two submitters and a likely benign variant by one submitter (ClinVar ID: 228518). Computational predictors indicate that the variant is damaging, evidence that correlates with impact on CLDN14 function. Due to limited information and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time.

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