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

gnomAD frequency: 0.00011  dbSNP: rs751459058

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000200808	SCV000251375	pathogenic	not provided	2022-05-11	criteria provided, single submitter	clinical testing	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, 28043061, 26553276, 32989326, 29126765, 30177229, 21234346, 31683770, 32007496, 34426522)
Invitae	RCV000525331	SCV000652835	pathogenic	Combined oxidative phosphorylation defect type 14	2024-01-07	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 361 of the FARS2 protein (p.Pro361Leu). This variant is present in population databases (rs751459058, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of FARS2-related conditions (PMID: 29126765, 32007496, 32989326). 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: 214335). 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) has been performed at Invitae 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. For these reasons, this variant has been classified as Pathogenic.
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München	RCV000525331	SCV000680227	pathogenic	Combined oxidative phosphorylation defect type 14	2017-11-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000622524	SCV000742958	likely pathogenic	Inborn genetic diseases	2023-05-03	criteria provided, single submitter	clinical testing	The c.1082C>T (p.P361L) alteration is located in exon 6 (coding exon 5) of the FARS2 gene. This alteration results from a C to T substitution at nucleotide position 1082, causing the proline (P) at amino acid position 361 to be replaced by a leucine (L). This variant has been reported with a second FARS2 variant in several unrelated individuals with clinical features of mitochondrial phenylalanyl-tRNA synthetase deficiency (Ambry internal data; Meszarosova, 2020). This variant has been detected as a homozygous finding in an individual with hypotonic cerebral palsy, dysgenesis of the corpus callosum, colpocephaly, diminished periventricular white matter volume, periventricular leukomalacia, and intellectual disability (Jin, 2020). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000525331	SCV000845716	likely pathogenic	Combined oxidative phosphorylation defect type 14	2018-06-13	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000578164	SCV001526168	pathogenic	Hereditary spastic paraplegia 77		criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000200808	SCV002064423	likely pathogenic	not provided	2020-08-05	criteria provided, single submitter	clinical testing	The sequence change, c.1082C>T, in exon 6 results in an amino acid change, p.Pro361Leu. The p.Pro361Leu change affects a highly conserved amino acid residue located in an anticodon binding domain of the FARS2 protein that is known to be functional. The p.Pro361Leu substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, REVEL). This particular amino acid change has been described in the compound heterozygous state in two unrelated patients with FARS2 deficiency with spastic paraplegia phenotype (PMID: 29126765). Functional studies using the fibroblasts from these individuals showed a decreased amount of Phe-charged tRNA and a decrease in mitochondrial protein synthesis rate, which affected the assembly of OXPHOS complexes (PMID: 29126765). This sequence change has been described in the gnomAD database with an overall low population frequency of 0.013%(dbSNP rs751459058).
3billion	RCV000578164	SCV002572742	likely pathogenic	Hereditary spastic paraplegia 77	2022-09-01	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.013%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.88; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000214335). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
Center for Personalized Medicine, Children's Hospital Los Angeles	RCV003156085	SCV003845274	likely pathogenic	See cases	2022-12-21	criteria provided, single submitter	clinical testing
Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL)	RCV000525331	SCV003920761	pathogenic	Combined oxidative phosphorylation defect type 14	2023-04-27	criteria provided, single submitter	research
OMIM	RCV000578164	SCV000680039	pathogenic	Hereditary spastic paraplegia 77	2018-01-30	no assertion criteria provided	literature only