Submissions for variant NM_006567.5(FARS2):c.1268G>A (p.Arg423Gln)

gnomAD frequency: 0.00016  dbSNP: rs148921184

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000198469	SCV000251377	uncertain significance	not provided	2019-10-29	criteria provided, single submitter	clinical testing	Reported in an individual with developmental delay and hypotonia in published literature (Kartvelishvili et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as R387Q due to alternative nomenclature; This variant is associated with the following publications: (PMID: 28419689)
Invitae	RCV000554776	SCV000652837	uncertain significance	Combined oxidative phosphorylation defect type 14	2022-07-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 423 of the FARS2 protein (p.Arg423Gln). This variant is present in population databases (rs148921184, gnomAD 0.02%). This missense change has been observed in individual(s) with developmental delay, hypotonia, and speech delay (PMID: 28419689). ClinVar contains an entry for this variant (Variation ID: 214337). 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. Experimental studies have shown that this missense change affects FARS2 function (PMID: 28419689). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000554776	SCV000845702	uncertain significance	Combined oxidative phosphorylation defect type 14	2018-06-13	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000554776	SCV001521060	uncertain significance	Combined oxidative phosphorylation defect type 14	2019-05-01	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Ambry Genetics	RCV002515395	SCV003737923	uncertain significance	Inborn genetic diseases	2022-01-06	criteria provided, single submitter	clinical testing	The c.1268G>A (p.R423Q) alteration is located in exon 7 (coding exon 6) of the FARS2 gene. This alteration results from a G to A substitution at nucleotide position 1268, causing the arginine (R) at amino acid position 423 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317145	SCV004021054	uncertain significance	not specified	2023-06-28	criteria provided, single submitter	clinical testing	Variant summary: FARS2 c.1268G>A (p.Arg423Gln) results in a conservative amino acid change located in the Ferrodoxin-fold anticodon-binding domain (IPR005121) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 251270 control chromosomes. c.1268G>A has been reported in the literature in individuals affected with developmental delay and hypotonia (Kartvelishvili_2017). This report does not provide unequivocal conclusions about association of the variant with FARS2-Related Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 28419689). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.