GARS1

protein-coding

glycyl-tRNA synthetase 1, the group of Aminoacyl tRNA synthetases, Class II

Gene summary

This gene encodes glycyl-tRNA synthetase, one of the aminoacyl-tRNA synthetases that charge tRNAs with their cognate amino acids. The encoded enzyme is an (alpha)2 dimer which belongs to the class II family of tRNA synthetases. It has been shown to be a target of autoantibodies in the human autoimmune diseases, polymyositis or dermatomyositis. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]

Previous symbols:

CMT2D
GARS

MANE transcript

NM_002047.4

Inheritance

AD, AR

ClinVar variants

P:46U:440B:206

Top phenotype

Charcot-Marie-Tooth disease, axonal, type 2D; Neuronopathy, distal hereditary motor, autosomal dominant 5; Spinal muscular atrophy, infantile, James type

gnomAD constraint

pLI —, LoF o/e 0.23

Max pathogenic AF

—

Genomic locus

chr7:30,580,533-30,634,033

External References & Databases

Ensembl (ENSG00000106105)

Transcript & Mutation Effects

hg38 • Region Span ~53.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neuronopathy, distal hereditary motor, type 5ASUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015353

Submitter: Orphanet

Charcot-Marie-Tooth disease type 2DSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011091

Submitter: Orphanet

mitochondrial diseaseMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: PanelApp Australia

neuronopathy, distal hereditary motor, type 5ASTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0015353

Submitter: Labcorp Genetics (formerly Invitae)

neuronopathy, distal hereditary motor, type 5ADEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015353

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

neuronopathy, distal hereditary motor, type 5ADEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015353

Submitter: Illumina

Charcot-Marie-Tooth disease type 2DDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011091

Submitter: ClinGen

GARS1 was described as the cause of Charcot Marie Tooth Disease type 2D (CMT2D) in five families in 2003 (Antonellis A. et al., 2003, PMID: 12690580). CMT2D is allelic with Distal Hereditary Motor Neuronopathy, type V-A, and infantile spinal muscular atrophy, James type. Phenotypical variability is thus present, however we found no difference in molecular mechanism and inheritance pattern. Therefore, the disease entities have been lumped into Charcot-Marie-Tooth disease. Patients with pathogenic GARS changes present with distal muscle weakness, distal amyotrophy, pes cavus, and intermediate slowing of the motor nerve conduction velocities upon EMG examination. Age-at-onset can be from congenital to juvenile, with a case reported as early as 6 weeks (PMID:32181591). GARS1 encodes glycine-tRNA synthetase 1, making it a member of the ubiquitously expressed aminoacyl tRNA synthetases responsible for charging tRNAs with their cognate amino acids. CMT2D-related mutations are missense changes or in-frame deletions. In total, we reviewed evidence for 14 variants, of which 5 were inherited in a de novo manner, adding up to a total of 12 points. Variants have been shown to impair yeast viability and to mislocalize in neuronal cell lines (Antonellis et al. 2006, PMID: 17035524, Nangle et al., 2007, PMID: 17595294). Through both mouse and drosophila models, it was shown that the phenotype is not caused by a loss of the GlyRS aminoacylation activity (Seburn et al., 2006, PMID: 16982418, Ermanoska et al., 2014, PMID: 24807208). All functional evidence summed up to 5.5 points. In summary, GARS1 is definitively associated with autosomal dominant Charcot-Marie-Tooth disease. This has been repeatedly demonstrated in both the research and diagnostic settings, and has been upheld over time.

Charcot-Marie-Tooth disease type 2DSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011091

Submitter: PanelApp Australia

Charcot-Marie-Tooth disease type 2DSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011091

Submitter: Labcorp Genetics (formerly Invitae)

spinal muscular atrophy, infantile, James typeMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0033621

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Charcot-Marie-Tooth disease, axonal, type 2D; Neuronopathy, distal hereditary motor, autosomal dominant 5; Spinal muscular atrophy, infantile, James typeAD

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 8541851; 8872480; 10732809; 9879677; 12690580; 16769947; 19329989; 20169446; 20301420; 20301462; 22462675; 23279345; 32181591

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GARS1 variants in ClinVar

24 Conditions Cataloged

Charcot-Marie-Tooth disease type 2Total: 631

not providedTotal: 225

not specifiedTotal: 218

Charcot-Marie-Tooth disease type 2DTotal: 80

Charcot-Marie-Tooth diseaseTotal: 61

Neuronopathy, distal hereditary motor, type 5ATotal: 58

GARS1-related disorderTotal: 57

Distal spinal muscular atrophyTotal: 44

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002047.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			5 clinvar	154 clinvar	4 clinvar	163
missense	12 clinvar	27 clinvar	391 clinvar	45 clinvar	3 clinvar	478
nonsense	1 clinvar	1 clinvar	11 clinvar			13
start loss			3 clinvar			3
frameshift	1 clinvar	1 clinvar	13 clinvar			15
splice donor/acceptor (+/-2bp)		3 clinvar	17 clinvar			20
Total	14	32	440	199	7	692

Highest pathogenic variant AF is 0.000010572376

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 33 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002047.4	RefSeq	NP_002038.2	17	MANE Select
ENST00000389266.8	Ensembl	ENSP00000373918.3	17	MANE Select
NM_001316772.1	RefSeq	NP_001303701.1	17	Standard
ENST00000444666.6	Ensembl	ENSP00000415447.2	14	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
gars	Danio rerio	Structure: CaP motoneuron Quality: decreased length abnormal

Gene / Model

Organism

Observed Phenotype

gars

Danio rerio

Structure: CaP motoneuron

Quality: decreased length

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Aminoacyl-tRNA biosynthesis - Homo sapiens (human)
3-Phosphoglycerate dehydrogenase deficiency
Non Ketotic Hyperglycinemia
Glycine and Serine Metabolism
Dimethylglycine Dehydrogenase Deficiency

Biological Process

tRNA aminoacylation for protein translation
glycyl-tRNA aminoacylation
diadenosine tetraphosphate biosynthetic process
mitochondrial glycyl-tRNA aminoacylation

Molecular Function

bis(5'-nucleosyl)-tetraphosphatase (asymmetrical) activity
glycine-tRNA ligase activity
protein binding
ATP binding
identical protein binding

Cellular Component

cytoplasm
mitochondrion
mitochondrial matrix
cytosol
secretory granule

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000389266
Coding exons: 17
Length: 39353
Individuals with no LoFs: 124782
Homozygous LoFs: 0
Heterozygous LoFs: 16
Defined: 124798
p: 0.0000641

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.20	334	402	0.832	0.0000216	4828
Missense (PolyPhen)		91	156.06	0.5831		1884
Synonymous	-0.186	151	148	1.02	0.00000783	1417
Loss of Function	4.46	9	39.1	0.230	0.00000232	444

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00017	0.00017	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000062	0.000062	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes the ligation of glycine to the 3'-end of its cognate tRNA. Also produces diadenosine tetraphosphate (Ap4A), a universal pleiotropic signaling molecule needed for cell regulation pathways, by direct condensation of 2 ATPs. {ECO:0000269|PubMed:17544401, ECO:0000269|PubMed:19710017, ECO:0000269|PubMed:28675565}.;
Disease: DISEASE: Neuronopathy, distal hereditary motor, 5A (HMN5A) [MIM:600794]: A disorder characterized by distal muscular atrophy mainly affecting the upper extremities, in contrast to other distal motor neuronopathies. These constitute a heterogeneous group of neuromuscular diseases caused by selective degeneration of motor neurons in the anterior horn of the spinal cord, without sensory deficit in the posterior horn. The overall clinical picture consists of a classical distal muscular atrophy syndrome in the legs without clinical sensory loss. The disease starts with weakness and wasting of distal muscles of the anterior tibial and peroneal compartments of the legs. Later on, weakness and atrophy may expand to the proximal muscles of the lower limbs and/or to the distal upper limbs. {ECO:0000269|PubMed:12690580, ECO:0000269|PubMed:17035524, ECO:0000269|PubMed:23279345, ECO:0000269|PubMed:24627108, ECO:0000269|PubMed:26503042}. Note=The disease is caused by mutations affecting the gene represented in this entry. Contrary to the wild-type protein, HMN5A variant Pro-183 strongly interacts with NRP1. This interaction may compete out VEGFA binding and inhibits VEGFA-NRP1 signling which is essential for motor neuron survival, as suggested by experiments done in a mouse model. {ECO:0000269|PubMed:26503042}.;

Recessive Scores

pRec: 0.0942

Intolerance Scores

LoFtool: 0.290
RVIS EVS: -0.71
RVIS percentile EVS: 14.57

Essentials

Essential (CRISPR): N
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.994

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium