UniProtKB/SwissProt variant VAR

Variant information

Variant position:

580

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 Glycine (G) to Arginine (R) at position 580 (G580R, p.Gly580Arg).

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 glycine (G) to large size and basic (R)

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:

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}.

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 HMN5A; higher dimerization stability; loss of activity; shows a large reduction in aminoacylation activity.

Any additional useful information about the variant.

Other resources:

Links to websites of interest for the variant.

Variant rs137852646 [ dbSNP | Ensembl ]

Sequence information

Variant position:

580

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:

RFQKTLYVEEVVPNVIEPSF G LGRIMYTVFEHTFHVREGDE

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                         RFQKTLYVEEVVPNVIEPSFGLGRIMYTVFEHTFHVREGDE

Mouse                         RFQKTLHVEEVVPSVIEPSFGLGRIMYTILEHTFHVREGDE

Caenorhabditis elegans        KYTKKIHVQEITPSVIEPSYGIGRIMYALLEHSFRQREGDE

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.

Type	Positions	Description
Chain	1 – 739	Glycine--tRNA ligase
Binding site	583 – 583	ATP
Beta strand	573 – 580

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;

Long-range structural effects of a Charcot-Marie-Tooth disease-causing mutation in human glycyl-tRNA synthetase.
Xie W.; Nangle L.A.; Zhang W.; Schimmel P.; Yang X.-L.;
Proc. Natl. Acad. Sci. U.S.A. 104:9976-9981(2007)
Cited for: X-RAY CRYSTALLOGRAPHY (2.85 ANGSTROMS) OF 55-739; VARIANT ARG-580; SUBUNIT;

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;

UniProtKB/Swiss-Prot P41250: Variant p.Gly580Arg