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UniProtKB/Swiss-Prot P41250: Variant p.Glu125Gly

Glycine--tRNA ligase
Gene: GARS
Chromosomal location: 7p15
Variant information

Variant position:  125
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Type of variant:  Disease [Disclaimer]
The variants are classified into three categories: Disease, Polymorphism and Unclassified.
  • Disease: Variants implicated in disease according to literature reports.
  • Polymorphism: Variants not reported to be implicated in disease.
  • Unclassified: Variants with uncertain implication in disease according to literature reports. Evidence against or in favor of a pathogenic role is limited and/or conflicting.

Residue change:  From Glutamate (E) to Glycine (G) at position 125 (E125G, p.Glu125Gly).
Indicates the amino acid change of the variant. The one-letter and three-letter codes for amino acids used in UniProtKB/Swiss-Prot are those adopted by the commission on Biochemical Nomenclature of the IUPAC-IUB.

Physico-chemical properties:  Change from medium size and acidic (E) to glycine (G)
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  -2
The score within a Blosum matrix for the corresponding wild-type to variant amino acid change. The log-odds score measures the logarithm for the ratio of the likelihood of two amino acids appearing by chance. The Blosum62 substitution matrix is used. This substitution matrix contains scores for all possible exchanges of one amino acid with another:
  • Lowest score: -4 (low probability of substitution).
  • Highest score: 11 (high probability of substitution).
More information can be found on the following page

Involvement in disease:  Charcot-Marie-Tooth disease 2D (CMT2D) [MIM:601472]: A dominant axonal form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 group are characterized by signs of axonal degeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy. {ECO:0000269|PubMed:12690580, ECO:0000269|PubMed:17035524, ECO:0000269|PubMed:17101916, ECO:0000269|PubMed:17663003, ECO:0000269|PubMed:20169446, ECO:0000269|PubMed:24604904, ECO:0000269|PubMed:25168514, ECO:0000269|PubMed:26244500, ECO:0000269|PubMed:26503042}. Note=The disease is caused by mutations affecting the gene represented in this entry. Contrary to the wild-type protein, CMT2D variants Gly-125 and Arg-294 strongly interact 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}.
The name and a short description of the disease associated with the variant. For more information about the disease, the user can refer to OMIM, following the link provided after the disease acronym.

Variant description:  In CMT2D; phenotype overlapping with DSMA-V; complements the defect of the wild-type gene in yeast; contrary to the wild-type protein, strongly binds to NRP1 and competes with VEGFA for NRP1-binding.
Any additional useful information about the variant.

Other resources:  
Links to websites of interest for the variant.



Sequence information

Variant position:  125
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  739
The length of the canonical sequence.

Location on the sequence:   LEAKELALQPKDDIVDRAKM  E DTLKRRFFYDQAFAIYGGVS
The residue change on the sequence. Unless the variant is located at the beginning or at the end of the protein sequence, both residues upstream (20) and downstream (20) of the variant will be shown.

Residue conservation: 
The multiple alignment of the region surrounding the variant against various orthologous sequences.

Human                         LEAKELALQPKDDIVDRAKMEDTLKRRFFYDQAFAIYGGVS

Mouse                         LEAKELALQPKDDIVDRAKMEDTLKRRFFYDQAFAIYGGVS

Caenorhabditis elegans        LEDTEIALAPKEASFDRLKLEDLLKRRFFYDQSFAIYGGVT

Sequence annotation in neighborhood:  
The regions or sites of interest surrounding the variant. In general the features listed are posttranslational modifications, binding sites, enzyme active sites, local secondary structure or other characteristics reported in the cited references. The "Sequence annotation in neighborhood" lines have a fixed format:
  • Type: the type of sequence feature.
  • Positions: endpoints of the sequence feature.
  • Description: contains additional information about the feature.

TypePositionsDescription
Chain 1 – 739 Glycine--tRNA ligase
Helix 121 – 130


Literature citations

Functional analyses of glycyl-tRNA synthetase mutations suggest a key role for tRNA-charging enzymes in peripheral axons.
Antonellis A.; Lee-Lin S.Q.; Wasterlain A.; Leo P.; Quezado M.; Goldfarb L.G.; Myung K.; Burgess S.; Fischbeck K.H.; Green E.D.;
J. Neurosci. 26:10397-10406(2006)
Cited for: SUBCELLULAR LOCATION; VARIANTS CMT2D GLY-125 AND ARG-294; CHARACTERIZATION OF VARIANTS CMT2D GLY-125 AND ARG-294; VARIANTS HMN5A PRO-183; ARG-472 AND ARG-580; CHARACTERIZATION OF VARIANTS HMN5A PRO-183; ARG-472 AND ARG-580;

Impaired function is a common feature of neuropathy-associated glycyl-tRNA synthetase mutations.
Griffin L.B.; Sakaguchi R.; McGuigan D.; Gonzalez M.A.; Searby C.; Zuchner S.; Hou Y.M.; Antonellis A.;
Hum. Mutat. 35:1363-1371(2014)
Cited for: SUBCELLULAR LOCATION; VARIANTS CMT2D VAL-111; ASN-200; PHE-265; ARG-294; LEU-298; PHE-334; ARG-472; ASN-554; ARG-580 AND ALA-652; VARIANT LEU-635; CHARACTERIZATION OF VARIANTS CMT2D VAL-111; GLY-125; PRO-183; ASN-200; PHE-265; ARG-294; LEU-298; PHE-334; ARG-472; ASN-554; ARG-580 AND ALA-652; CHARACTERIZATION OF VARIANT LEU-635;

Glycyl tRNA synthetase mutations in Charcot-Marie-Tooth disease type 2D and distal spinal muscular atrophy type V.
Antonellis A.; Ellsworth R.E.; Sambuughin N.; Puls I.; Abel A.; Lee-Lin S.Q.; Jordanova A.; Kremensky I.; Christodoulou K.; Middleton L.T.; Sivakumar K.; Ionasescu V.; Funalot B.; Vance J.M.; Goldfarb L.G.; Fischbeck K.H.; Green E.D.;
Am. J. Hum. Genet. 72:1293-1299(2003)
Cited for: VARIANTS CMT2D GLY-125 AND ARG-294; VARIANTS HMN5A PRO-183 AND ARG-580; TISSUE SPECIFICITY;

CMT2D neuropathy is linked to the neomorphic binding activity of glycyl-tRNA synthetase.
He W.; Bai G.; Zhou H.; Wei N.; White N.M.; Lauer J.; Liu H.; Shi Y.; Dumitru C.D.; Lettieri K.; Shubayev V.; Jordanova A.; Guergueltcheva V.; Griffin P.R.; Burgess R.W.; Pfaff S.L.; Yang X.L.;
Nature 526:710-714(2015)
Cited for: CHARACTERIZATION OF VARIANTS CMT2D GLY-125 AND ARG-294; CHARACTERIZATION OF VARIANT HMN5A PRO-183;

Disclaimer: Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. They are not in any way intended to be used as a substitute for professional medical advice, diagnostic, treatment or care.