Submissions for variant NM_006567.5(FARS2):c.667C>T (p.Arg223Cys)

gnomAD frequency: 0.00028  dbSNP: rs202060864

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000196357	SCV000251370	uncertain significance	not provided	2020-12-17	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 32597768)
Invitae	RCV000650594	SCV000772441	uncertain significance	Combined oxidative phosphorylation defect type 14	2022-08-12	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 223 of the FARS2 protein (p.Arg223Cys). This variant is present in population databases (rs202060864, gnomAD 0.2%). This missense change has been observed in individual(s) with epileptic encephalopathy (PMID: 32597768). ClinVar contains an entry for this variant (Variation ID: 214330). 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.
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV000650594	SCV001164195	likely pathogenic	Combined oxidative phosphorylation defect type 14	2018-04-10	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000196357	SCV001549974	uncertain significance	not provided		no assertion criteria provided	clinical testing	The FARS2 p.Arg223Cys variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs202060864), ClinVar (classified as likely pathogenic by GeneDx and uncertain significance by Invitae. The variant was identified in control databases in 76 of 281418 chromosomes at a frequency of 0.0002701 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (Finnish) in 47 of 25106 chromosomes (freq: 0.001872), Ashkenazi Jewish in 10 of 10350 chromosomes (freq: 0.000966), European (non-Finnish) in 17 of 128836 chromosomes (freq: 0.000132) and African in 2 of 24928 chromosomes (freq: 0.00008), but was not observed in the Latino, East Asian, Other or South Asian populations. The p.Arg223 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.