ClinVar Miner

Submissions for variant NM_024537.4(CARS2):c.1646C>T (p.Thr549Met)

gnomAD frequency: 0.00004  dbSNP: rs371625448
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001756877 SCV001995111 uncertain significance not provided 2019-11-01 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp RCV001868455 SCV002222834 uncertain significance Combined oxidative phosphorylation defect type 27 2022-10-13 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 549 of the CARS2 protein (p.Thr549Met). This variant is present in population databases (rs371625448, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with CARS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1309809). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CARS2 protein function. 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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