Submissions for variant NM_006567.5(FARS2):c.407C>A (p.Pro136His)

gnomAD frequency: 0.00022  dbSNP: rs199863563

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000542910	SCV000652842	pathogenic	Combined oxidative phosphorylation defect type 14	2025-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 136 of the FARS2 protein (p.Pro136His). This variant is present in population databases (rs199863563, gnomAD 0.6%). This missense change has been observed in individual(s) with autosomal recessive spastic paraplegia (PMID: 30250868; external communication). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 473309). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FARS2 protein function. Experimental studies have shown that this missense change affects FARS2 function (PMID: 30250868). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001545144	SCV001764416	pathogenic	not provided	2024-05-23	criteria provided, single submitter	clinical testing	Functional studies show that this variant is associated with significantly reduced enzyme activity compared to wild type (PMID: 30250868); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30250868, 31692161, 37152989, 35794642, 38166857)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005056163	SCV005725621	likely pathogenic	FARS2-related disorder	2024-11-27	criteria provided, single submitter	clinical testing	Variant summary: FARS2 c.407C>A (p.Pro136His) results in a non-conservative amino acid change located in the tRNA synthetases class II core domain (F) (IPR002319) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00031 in 251328 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in FARS2 causing FARS2-Related Disorders, allowing no conclusion about variant significance. c.407C>A has been reported in the presumed compound heterozygous state literature in individuals affected with FARS2-Related Disorders (example, Ngo_2020, Sahai_2018), including at least 1 individual carrying a pathogenic variant in trans. These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% catalytic efficiency in vitro (example, Sahai_2018). The following publications have been ascertained in the context of this evaluation (PMID: 31692161, 30250868). ClinVar contains an entry for this variant (Variation ID: 473309). Based on the evidence outlined above, the variant was classified as likely pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001545144	SCV005879261	likely pathogenic	not provided	2024-05-14	criteria provided, single submitter	clinical testing	The FARS2 c.407C>A; p.Pro136His variant (rs199863563; ClinVar Variation ID: 473309) is reported in the literature in two individuals affected with spastic paraplegia/spinocerebellar ataxia (Sahai 2018 and Ngo 2020). In both of these reported patients, the p.Pro136His variant was found in combination with additional pathogenic alleles of FARS2. This variant is found in the Ashkenazi Jewish population with an allele frequency of 0.63% (65/10,366 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses predict that this variant is deleterious (REVEL: 0.772). And functional analyses of the variant protein show reduced aminoacylation activity compared to wild-type (Sahai 2018). This variant is located in the catalytic domain of FARS2, and missense variants located in nearby residues have been reported in similarly affected patients (c.403C>G; p.His135Asp and c.422G>A; p.Gly141Glu; Walker 2016 and Forman 2019). Based on available information, the p.Pro136His variant is considered to be likely pathogenic. References: Forman EB et al. FARS2 Causing Complex Hereditary Spastic Paraplegia With Dysphonia: Expanding the Disease Spectrum. J Child Neurol. 2019 Sep;34(10):621. PMID: 31106652. Ngo KJ et al. A diagnostic ceiling for exome sequencing in cerebellar ataxia and related neurological disorders. Hum Mutat. 2020 Feb;41(2):487-501. PMID: 31692161 Sahai SK et al. FARS2 mutations presenting with pure spastic paraplegia and lesions of the dentate nuclei. Ann Clin Transl Neurol. 2018 Aug 14;5(9):1128-1133. PMID: 30250868 Walker MA et al. Novel Compound Heterozygous Mutations Expand the Recognized Phenotypes of FARS2-Linked Disease. J Child Neurol. 2016 Aug;31(9):1127-37. PMID: 27095821
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV005398839	SCV006054998	pathogenic	Combined oxidative phosphorylation defect type 14; Hereditary spastic paraplegia 77	2023-07-24	criteria provided, single submitter	research
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000542910	SCV000845676	uncertain significance	Combined oxidative phosphorylation defect type 14	2018-06-13	flagged submission	clinical testing