Submissions for variant NM_006567.5(FARS2):c.989G>A (p.Arg330His)

gnomAD frequency: 0.00005  dbSNP: rs863223957

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000677021	SCV000251374	uncertain significance	not provided	2015-10-19	criteria provided, single submitter	clinical testing	The R330H variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R330H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (D325Y, I329T) have been reported in the Human Gene Mutation Database in association with infantile-onset epilepsy and the mitochondrial encephalopathy, fatal infantile Alpers (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV001215842	SCV001387606	uncertain significance	Combined oxidative phosphorylation defect type 14	2022-07-20	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 330 of the FARS2 protein (p.Arg330His). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of FARS2-related conditions (PMID: 33168986). ClinVar contains an entry for this variant (Variation ID: 214334). 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. 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000677021	SCV000802854	uncertain significance	not provided	2017-08-04	no assertion criteria provided	clinical testing
Laboratoire de Génétique Moléculaire Institut de Recherche Necker Enfants Malades, CHU Paris - Hôpital Necker-Enfants Malades	RCV001215842	SCV001424745	pathogenic	Combined oxidative phosphorylation defect type 14	2019-12-12	no assertion criteria provided	clinical testing