GARS1

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

Basic information

Region (hg38): 7:30580532-30634033

Previous symbols: [ "CMT2D", "GARS" ]

Links

ENSG00000106105 ∙ NCBI:2617 ∙ OMIM:600287 ∙ HGNC:4162 ∙ Uniprot:P41250 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Charcot-Marie-Tooth disease type 2D (Supportive), mode of inheritance: AD
• neuronopathy, distal hereditary motor, type 5A (Supportive), mode of inheritance: AD
• neuronopathy, distal hereditary motor, type 5A (Definitive), mode of inheritance: AD
• spinal muscular atrophy, infantile, James type (Moderate), mode of inheritance: AD
• neuronopathy, distal hereditary motor, type 5A (Definitive), mode of inheritance: AD
• neuronopathy, distal hereditary motor, type 5A (Strong), mode of inheritance: AD
• Charcot-Marie-Tooth disease type 2D (Strong), mode of inheritance: AD
• Charcot-Marie-Tooth disease type 2D (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Charcot-Marie-Tooth disease, axonal, type 2D; Neuronopathy, distal hereditary motor, autosomal dominant 5; Spinal muscular atrophy, infantile, James type	AD	General	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	Neurologic	8541851; 8872480; 10732809; 9879677; 12690580; 16769947; 19329989; 20169446; 20301420; 20301462; 22462675; 23279345; 32181591

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the GARS1 gene.

• Charcot-Marie-Tooth disease type 2 (496 variants)
• not provided (202 variants)
• Inborn genetic diseases (108 variants)
• Charcot-Marie-Tooth disease type 2D (83 variants)
• Neuronopathy, distal hereditary motor, type 5A (77 variants)
• Distal spinal muscular atrophy (69 variants)
• Charcot-Marie-Tooth disease (63 variants)
• not specified (59 variants)
• Neuronopathy, distal hereditary motor, type 5 (5 variants)
• Spinal muscular atrophy, infantile, James type (5 variants)
• Charcot-Marie-Tooth disease type 2D;Neuronopathy, distal hereditary motor, type 5A (4 variants)
• Neuronopathy, distal hereditary motor, type 5A;Charcot-Marie-Tooth disease type 2D (3 variants)
• GARS-Associated Axonal Neuropathy (2 variants)
• See cases (2 variants)
• Tip-toe gait (1 variants)
• Charcot-Marie-Tooth disease, type I (1 variants)
• GARS1-related neuropathies (1 variants)
• GARS1-related condition (1 variants)
• Charcot-Marie-Tooth disease type 5 (1 variants)
• GARS-associated growth retardation and developmental delay (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the GARS1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			7	108	6	121
missense	11	10	259	11	3	294
nonsense	1		8			9
start loss			2			2
frameshift		1	6			7
inframe indel			7		1	8
splice donor/acceptor (+/-2bp)		1	5			6
splice region			13	9	2	24
non coding			21	80	39	140
Total	12	12	315	199	49

Variants in GARS1

This is a list of pathogenic ClinVar variants found in the GARS1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
7-30594388-T-C			Benign (Jun 14, 2018)
7-30594476-T-C			Likely benign (Aug 07, 2018)
7-30594504-T-A			Benign (Jun 14, 2018)
7-30594605-G-A		Neuronopathy, distal hereditary motor, type 5A • Distal spinal muscular atrophy • Charcot-Marie-Tooth disease type 2D	Benign (Jun 14, 2018)
7-30594642-G-A		Neuronopathy, distal hereditary motor, type 5A • Charcot-Marie-Tooth disease type 2D • Distal spinal muscular atrophy	Benign (Jan 13, 2018)
7-30594685-A-C		Neuronopathy, distal hereditary motor, type 5A • Distal spinal muscular atrophy • Charcot-Marie-Tooth disease type 2D	Uncertain significance (Jan 13, 2018)
7-30594697-G-A		Distal spinal muscular atrophy • Neuronopathy, distal hereditary motor, type 5A • Charcot-Marie-Tooth disease type 2D	Benign/Likely benign (Jun 16, 2018)
7-30594705-A-G		Neuronopathy, distal hereditary motor, type 5A • Distal spinal muscular atrophy • Charcot-Marie-Tooth disease type 2D	Benign (Jun 16, 2018)
7-30594717-C-T		Distal spinal muscular atrophy • Neuronopathy, distal hereditary motor, type 5A • Charcot-Marie-Tooth disease type 2D	Benign/Likely benign (Jun 14, 2018)
7-30594725-G-C		Distal spinal muscular atrophy • Neuronopathy, distal hereditary motor, type 5A • Charcot-Marie-Tooth disease type 2D	Uncertain significance (Jan 12, 2018)
7-30594727-A-T		Neuronopathy, distal hereditary motor, type 5A • Charcot-Marie-Tooth disease type 2D • Distal spinal muscular atrophy	Uncertain significance (Jan 13, 2018)
7-30594742-G-C		Distal spinal muscular atrophy • Neuronopathy, distal hereditary motor, type 5A • Charcot-Marie-Tooth disease type 2D	Uncertain significance (Jan 13, 2018)
7-30594745-T-C		Distal spinal muscular atrophy • Neuronopathy, distal hereditary motor, type 5A • Charcot-Marie-Tooth disease type 2D	Benign/Likely benign (Apr 01, 2023)
7-30594756-T-G		Distal spinal muscular atrophy • Charcot-Marie-Tooth disease type 2D • Neuronopathy, distal hereditary motor, type 5A	Uncertain significance (Jan 13, 2018)
7-30594837-C-A		Charcot-Marie-Tooth disease type 2D • Neuronopathy, distal hereditary motor, type 5A • Distal spinal muscular atrophy	Conflicting classifications of pathogenicity (Aug 14, 2018)
7-30594842-C-T		Neuronopathy, distal hereditary motor, type 5A • Distal spinal muscular atrophy • Charcot-Marie-Tooth disease type 2D	Uncertain significance (Jan 13, 2018)
7-30594853-T-A		Charcot-Marie-Tooth disease type 2D • Distal spinal muscular atrophy • Neuronopathy, distal hereditary motor, type 5A	Benign (Jan 13, 2018)
7-30594853-T-G		Distal spinal muscular atrophy • Neuronopathy, distal hereditary motor, type 5A • Charcot-Marie-Tooth disease type 2D	Uncertain significance (Jan 13, 2018)
7-30594858-C-T		Neuronopathy, distal hereditary motor, type 5A • Distal spinal muscular atrophy • Charcot-Marie-Tooth disease type 2D	Uncertain significance (Jan 13, 2018)
7-30594863-C-T		Distal spinal muscular atrophy • Neuronopathy, distal hereditary motor, type 5A • Charcot-Marie-Tooth disease type 2D	Uncertain significance (Jan 13, 2018)
7-30594877-C-G		Charcot-Marie-Tooth disease type 2D;Neuronopathy, distal hereditary motor, type 5A	not provided (-)
7-30594877-C-T			Uncertain significance (May 15, 2018)
7-30594882-C-A		not specified	Likely benign (Jul 31, 2017)
7-30594884-G-A			Uncertain significance (Jan 04, 2017)
7-30594886-C-A		Distal spinal muscular atrophy • Charcot-Marie-Tooth disease type 2D • Neuronopathy, distal hereditary motor, type 5A	Benign/Likely benign (Jan 12, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
GARS1	protein_coding	protein_coding	ENST00000389266	17	39353

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.306	0.694	124782	0	16	124798	0.0000641

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.20	334	402	0.832	0.0000216	4828
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000116	0.000116
Ashkenazi Jewish	0.0000993	0.0000993
East Asian	0.000167	0.000167
Finnish	0.0000464	0.0000464
European (Non-Finnish)	0.0000618	0.0000618
Middle Eastern	0.000167	0.000167
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

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}.
• Pathway: Aminoacyl-tRNA biosynthesis - Homo sapiens (human);3-Phosphoglycerate dehydrogenase deficiency;Non Ketotic Hyperglycinemia;Glycine and Serine Metabolism;Dimethylglycine Dehydrogenase Deficiency;Hyperglycinemia, non-ketotic;Dimethylglycine Dehydrogenase Deficiency;Sarcosinemia;Dihydropyrimidine Dehydrogenase Deficiency (DHPD);tRNA Aminoacylation;Translation;Metabolism of proteins;Glycine Serine metabolism;tRNA charging;Cytosolic tRNA aminoacylation;Mitochondrial tRNA aminoacylation (Consensus)

Recessive Scores

• pRec: 0.0942

Intolerance Scores

• loftool: 0.290
• rvis_EVS: -0.71
• rvis_percentile_EVS: 14.57

Haploinsufficiency Scores

• pHI: 0.327
• hipred: Y
• hipred_score: 0.650
• ghis: 0.537

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.994

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Gars
• Phenotype: nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); normal phenotype; growth/size/body region phenotype; muscle phenotype

Zebrafish Information Network

• Gene name: gars
• Affected structure: CaP motoneuron
• Phenotype tag: abnormal
• Phenotype quality: decreased length

Gene ontology

• Biological process: tRNA aminoacylation for protein translation;glycyl-tRNA aminoacylation;diadenosine tetraphosphate biosynthetic process;mitochondrial glycyl-tRNA aminoacylation
• Cellular component: cytoplasm;mitochondrion;mitochondrial matrix;cytosol;secretory granule;axon;extracellular exosome
• Molecular function: bis(5'-nucleosyl)-tetraphosphatase (asymmetrical) activity;glycine-tRNA ligase activity;protein binding;ATP binding;identical protein binding;protein dimerization activity