NM_006567.5:c.1082C>T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1PP3_StrongPP5_Very_Strong

The NM_006567.5(FARS2):c.1082C>T(p.Pro361Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000218 in 1,612,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P361P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00023 ( 0 hom. )

Consequence

FARS2
NM_006567.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 7.20

Publications

10 publications found

Variant links:

Genes affected

FARS2 (HGNC:21062): (phenylalanyl-tRNA synthetase 2, mitochondrial) This gene encodes a protein that transfers phenylalanine to its cognate tRNA. This protein localizes to the mitochondrion and plays a role in mitochondrial protein translation. Mutations in this gene can cause combined oxidative phosphorylation deficiency 14 (Alpers encephalopathy). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

FARS2 Gene-Disease associations (from GenCC):

metabolic disease
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
combined oxidative phosphorylation defect type 14
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
hereditary spastic paraplegia 77
Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
Leigh syndrome
Inheritance: AR Classification: MODERATE Submitted by: ClinGen

FARS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PM1

In a domain FDX-ACB (size 92) in uniprot entity SYFM_HUMAN there are 10 pathogenic changes around while only 2 benign (83%) in NM_006567.5

PP3

MetaRNN computational evidence supports a deleterious effect, 0.99

PP5

Variant 6-5613185-C-T is Pathogenic according to our data. Variant chr6-5613185-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 214335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FARS2	NM_006567.5 link	c.1082C>T	p.Pro361Leu	missense_variant	Exon 6 of 7	ENST00000274680.9	NP_006558.1	O95363

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FARS2	ENST00000274680.9 link	c.1082C>T	p.Pro361Leu	missense_variant	Exon 6 of 7	1	NM_006567.5	ENSP00000274680.4	O95363
FARS2	ENST00000324331.10 link	c.1082C>T	p.Pro361Leu	missense_variant	Exon 6 of 7	1		ENSP00000316335.5	O95363
FARS2	ENST00000648580.1 link	n.1082C>T		non_coding_transcript_exon_variant	Exon 6 of 9			ENSP00000497889.1	A0A3B3ITR6

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000136

AC:

AN:

250446

AF XY:

0.000140

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000380

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000141

Gnomad OTH exome

AF:

0.000328

GnomAD4 exome

AF:

0.000230

AC:

336

AN:

1460054

Hom.:

Cov.:

AF XY:

0.000213

AC XY:

155

AN XY:

726450

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33418

American (AMR)

AF:

0.000405

AC:

AN:

44434

Ashkenazi Jewish (ASJ)

AF:

0.000191

AC:

AN:

26114

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39562

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86034

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53248

Middle Eastern (MID)

AF:

0.000868

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000264

AC:

293

AN:

1111158

Other (OTH)

AF:

0.000199

AC:

AN:

60324

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000986

AC:

AN:

152080

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74278

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41408

American (AMR)

AF:

0.000131

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10586

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000165

Hom.:

Bravo

AF:

0.000125

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.000123

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000237

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Combined oxidative phosphorylation defect type 14

Pathogenic:4

Jun 13, 2018

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 16, 2017

Institute of Human Genetics Munich, TUM University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2023

Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Dec 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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 autosomal recessive 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). 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) indicates that this missense variant is expected to disrupt FARS2 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Hereditary spastic paraplegia 77

Pathogenic:3

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 30, 2018

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Sep 01, 2022

3billion

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method: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. -

not provided

Pathogenic:3

Jan 27, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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, 26553276, 29126765, 21234346, 31683770, 32007496, 34426522, 37541188, 36781956, 28043061, 32989326, 30177229, 37152989, 36603837, 35794642, 39342436, 38166857, 38360210) -

Aug 05, 2020

Genetic Services Laboratory, University of Chicago

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method: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). -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

FARS2: PM3:Strong, PM2, PP4, PS3:Supporting -

FARS2-related disorder

Pathogenic:1

Sep 16, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The FARS2 c.1082C>T variant is predicted to result in the amino acid substitution p.Pro361Leu. This variant has been reported in the compound heterozygous or homozygous state in patients with spastic paraplegia (Vantroys et al. 2017. PubMed ID: 29126765; Meszarosova et al. 2020. PubMed ID: 32007496; Jin et al. 2020. PubMed ID: 32989326, Supplementary Table 7), as well as combined oxidative phosphorylation deficiency 14 (Bravo-Alonso et al. 2019. PubMed ID: 31683770). This variant has been classified as pathogenic or likely pathogenic by multiple independent submitters to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/214335/). This variant is reported in 0.040% of alleles in individuals of Latino descent in gnomAD. Based on the collective information, this variant is interpreted as likely pathogenic. -

Inborn genetic diseases

Pathogenic:1

May 03, 2023

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method: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. -

See cases

Pathogenic:1

Dec 21, 2022

Center for Personalized Medicine, Children's Hospital Los Angeles

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Combined oxidative phosphorylation defect type 14;C5569007:Hereditary spastic paraplegia 77

Pathogenic:1

May 26, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

D;D

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

.;D

M_CAP

Pathogenic

0.30

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

0.87

MutationAssessor

Pathogenic

3.5

H;H

PhyloP100

7.2

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-9.2

D;D

REVEL

Pathogenic

0.88

Sift

Benign

0.047

D;D

Sift4G

Uncertain

0.024

D;D

Polyphen

1.0

D;D

Vest4

1.0

MVP

0.99

MPC

0.62

ClinPred

1.0

GERP RS

5.5

Varity_R

0.90

gMVP

0.87

Mutation Taster

=3/97

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over