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UniProtKB/Swiss-Prot P12081: Variant p.Asp175Glu

Histidine--tRNA ligase, cytoplasmic
Gene: HARS
Chromosomal location: 5q31.3
Variant information

Variant position:  175
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 Aspartate (D) to Glutamate (E) at position 175 (D175E, p.Asp175Glu).
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:  Similar physico-chemical property. Both residues are medium size and acidic.
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 2W (CMT2W) [MIM:616625]: An autosomal 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. CMT2W patients manifest a peripheral neuropathy mainly affecting the lower limbs and resulting in gait difficulties and distal sensory impairment. Most patients also have upper limb involvement. {ECO:0000269|PubMed:22930593, ECO:0000269|PubMed:26072516}. Note=The disease is caused by mutations affecting the gene represented in this entry.
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 CMT2W; hypomorphic mutation.
Any additional useful information about the variant.

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



Sequence information

Variant position:  175
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  509
The length of the canonical sequence.

Location on the sequence:   VYRRDNPAMTRGRYREFYQC  D FDIAGNFDPMIPDAECLKIM
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                         VYRRDNPAMTRGRYREFYQCDFDIAGNFDPMIPDAECLKIM

Mouse                         VYRRDNPAMTRGRYREFYQCDFDIAGQFDPMIPDAECLKIM

Bovine                        VYRRDNPAMTRGRYREFYQCDFDIAGQFDPMLPDAECLKIM

Slime mold                    VYRRDNPIMTKGRFREFYQCDFDIAGTYDLMVPDAECLVMI

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 2 – 509 Histidine--tRNA ligase, cytoplasmic
Binding site 157 – 157 L-histidine
Binding site 173 – 173 L-histidine
Binding site 177 – 177 L-histidine
Beta strand 169 – 180


Literature citations

Loss of function mutations in HARS cause a spectrum of inherited peripheral neuropathies.
Safka Brozkova D.; Deconinck T.; Griffin L.B.; Ferbert A.; Haberlova J.; Mazanec R.; Lassuthova P.; Roth C.; Pilunthanakul T.; Rautenstrauss B.; Janecke A.R.; Zavadakova P.; Chrast R.; Rivolta C.; Zuchner S.; Antonellis A.; Beg A.A.; De Jonghe P.; Senderek J.; Seeman P.; Baets J.;
Brain 138:2161-2172(2015)
Cited for: FUNCTION; INVOLVEMENT IN CMT2W; VARIANTS CMT2W ILE-132; HIS-134; GLU-175 AND TYR-364; CHARACTERIZATION OF VARIANTS CMT2W ILE-132; HIS-134; GLU-175 AND TYR-364;

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.