ClinVar Miner

Submissions for variant NM_006567.5(FARS2):c.1082C>T (p.Pro361Leu) (rs751459058)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000200808 SCV000251375 likely pathogenic not provided 2018-09-12 criteria provided, single submitter clinical testing The P361L variant in the FARS2 gene has been reported previously in the compound heterozygous state with another FARS2 variant in two unrelated individuals with clinical features associated with combined oxidative phosphorylation deficiency-14 (Vantroys et al., 2017). The P361L variant is observed in 15/34090 (0.044%) alleles from individuals of Latino background, and 37/276242 total alleles in large population cohorts (Lek et al., 2016). The P361L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret P361L as a likely pathogenic variant.
Invitae RCV000525331 SCV000652835 likely pathogenic Combined oxidative phosphorylation deficiency 14 2020-10-05 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 361 of the FARS2 protein (p.Pro361Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs751459058, ExAC 0.03%). This variant has been observed in individual(s) with clinical features of FARS2-related conditions (PMID: 29126765, 32007496). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 214335). 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.
Institute of Human Genetics, Klinikum rechts der Isar RCV000525331 SCV000680227 pathogenic Combined oxidative phosphorylation deficiency 14 2017-11-16 criteria provided, single submitter clinical testing
Ambry Genetics RCV000622524 SCV000742958 uncertain significance Inborn genetic diseases 2017-09-25 criteria provided, single submitter clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000525331 SCV000845716 likely pathogenic Combined oxidative phosphorylation deficiency 14 2018-06-13 criteria provided, single submitter clinical testing
Baylor Genetics RCV000578164 SCV001526168 uncertain significance Spastic paraplegia 77, autosomal recessive 2018-11-08 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
OMIM RCV000578164 SCV000680039 pathogenic Spastic paraplegia 77, autosomal recessive 2018-01-30 no assertion criteria provided literature only

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