ClinVar Miner

Submissions for variant NM_006567.5(FARS2):c.431A>G (p.Tyr144Cys) (rs397514610)

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Total submissions: 7
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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 deficiency 14 2018-06-13 criteria provided, single submitter clinical testing
OMIM RCV000033044 SCV000056824 pathogenic Combined oxidative phosphorylation deficiency 14 2012-10-15 no assertion criteria provided literature only
Developmental Genetics Unit,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 deficiency 14 2016-01-10 no assertion criteria provided research
GeneReviews RCV000033044 SCV000891737 pathogenic Combined oxidative phosphorylation deficiency 14 2019-01-24 no assertion criteria provided literature only
Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical City RCV000033044 SCV001133175 likely pathogenic Combined oxidative phosphorylation deficiency 14 2019-09-26 no assertion criteria provided clinical testing

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