ClinVar Miner

Submissions for variant NM_003680.4(YARS1):c.176T>C (p.Ile59Thr)

gnomAD frequency: 0.00001  dbSNP: rs774466323
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000698802 SCV000827488 uncertain significance Charcot-Marie-Tooth disease dominant intermediate C 2023-11-24 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 59 of the YARS protein (p.Ile59Thr). This variant is present in population databases (rs774466323, gnomAD 0.004%). This missense change has been observed in individual(s) with YARS-related multi-systemic syndrome (PMID: 34352414). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 576327). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt YARS protein function with a positive predictive value of 80%. Studies have shown that this missense change alters YARS gene expression (PMID: 34352414). 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.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV001813550 SCV002060436 likely pathogenic Neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 2 2022-01-18 criteria provided, single submitter clinical testing
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille RCV002274090 SCV002559152 likely pathogenic Neurodevelopmental delay criteria provided, single submitter clinical testing
Marseille Medical Genetics, U1251, Aix Marseille University, Inserm RCV000984016 SCV000924303 pathogenic recessive ARS-related multisystem disease no assertion criteria provided in vitro

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