ClinVar Miner

Submissions for variant NM_006567.5(FARS2):c.407C>A (p.Pro136His)

gnomAD frequency: 0.00022  dbSNP: rs199863563
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000542910 SCV000652842 pathogenic Combined oxidative phosphorylation defect type 14 2024-01-23 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 136 of the FARS2 protein (p.Pro136His). This variant is present in population databases (rs199863563, gnomAD 0.6%). This missense change has been observed in individual(s) with spastic paraplegia (PMID: 30250868; external communication). 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: 473309). 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 FARS2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects FARS2 function (PMID: 30250868). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV001545144 SCV001764416 pathogenic not provided 2024-05-23 criteria provided, single submitter clinical testing Functional studies show that this variant is associated with significantly reduced enzyme activity compared to wild type (PMID: 30250868); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30250868, 31692161, 37152989, 35794642, 38166857)
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000542910 SCV000845676 uncertain significance Combined oxidative phosphorylation defect type 14 2018-06-13 flagged submission clinical testing

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