ClinVar Miner

Submissions for variant NM_006567.5(FARS2):c.1255C>T (p.Arg419Cys) (rs775690041)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000197201 SCV000251376 likely pathogenic not provided 2016-10-19 criteria provided, single submitter clinical testing The R419C variant in the FARS2 gene has been reported previously in the compound heterozygous state with a FARS2 interstitial deletion in a sibling pair with mitochondrial dysfunction (Vernon et al., 2015). The R419C 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 R419C 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. In silico analysis predicts this variant is probably damaging to the protein structure/function. The R419C variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000578139 SCV000845719 likely pathogenic Spastic paraplegia 77, autosomal recessive 2018-06-13 criteria provided, single submitter clinical testing
Invitae RCV001378476 SCV001576048 likely pathogenic Combined oxidative phosphorylation deficiency 14 2020-03-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 419 of the FARS2 protein (p.Arg419Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs775690041, ExAC 0.003%). This variant has been observed in individual(s) with clinical features of hereditary spastic paraplegia (PMID: 25851414, 30177229). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 214336). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
OMIM RCV000578139 SCV000679998 pathogenic Spastic paraplegia 77, autosomal recessive 2018-01-30 no assertion criteria provided literature only

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