Submissions for variant NM_006567.5(FARS2):c.431A>G (p.Tyr144Cys)

dbSNP: rs397514610

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000497519	SCV000589666	likely pathogenic	not provided	2016-06-22	criteria provided, single submitter	clinical testing	The Y144C missense variant in the FARS2 gene has been identified through whole exome sequencing in the homozygous state in three siblings with mitochondrial encephalopathy (Shamseldin et al. 2012). Functional studies found that Y144C disrupts tRNA binding and stability of the mitochondrial phenylalanyl transfer RNA (tRNA) synthetase (mtPheRS) protein leading to a decrease in tRNA charging capacity (Elo et al. 2012). The Y144C variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Y144C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, we interpret this variant to be likely pathogenic. This finding is likely consistent with a diagnosis of combined oxidative phosphorylation deficiency-14 in this patient. However, this result could also be seen if the patient had one allele with the Y144C pathogenic variant and one allele that was partially missing or refractory to amplification.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000033044	SCV000845708	pathogenic	Combined oxidative phosphorylation defect type 14	2018-06-13	criteria provided, single submitter	clinical testing
Invitae	RCV000033044	SCV001389842	pathogenic	Combined oxidative phosphorylation defect type 14	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 144 of the FARS2 protein (p.Tyr144Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of early infantile epileptic encephalopathy (PMID: 22499341, 22833457, 30177229). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 39824). 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 95%. Experimental studies have shown that this missense change affects FARS2 function (PMID: 22833457). For these reasons, this variant has been classified as Pathogenic.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000033044	SCV005038812	pathogenic	Combined oxidative phosphorylation defect type 14	2024-03-14	criteria provided, single submitter	clinical testing
OMIM	RCV000033044	SCV000056824	pathogenic	Combined oxidative phosphorylation defect type 14	2012-10-15	no assertion criteria provided	literature only
Department Of Translational Genomics (developmental Genetics Section), King Faisal Specialist Hospital & Research Centre	RCV000162158	SCV000196444	likely pathogenic	Mitochondrial encephalomyopathy; Global developmental delay	2014-12-01	no assertion criteria provided	research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000033044	SCV000282188	pathogenic	Combined oxidative phosphorylation defect type 14	2016-01-10	no assertion criteria provided	research
GeneReviews	RCV000033044	SCV000891737	not provided	Combined oxidative phosphorylation defect type 14		no assertion provided	literature only
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000033044	SCV001133175	likely pathogenic	Combined oxidative phosphorylation defect type 14	2019-09-26	no assertion criteria provided	clinical testing