Home  |  Contact

UniProtKB/Swiss-Prot O95140: Variant p.Arg94Gln

Mitofusin-2
Gene: MFN2
Variant information

Variant position:  94
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 Arginine (R) to Glutamine (Q) at position 94 (R94Q, p.Arg94Gln).
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 large size and basic (R) to medium size and polar (Q)
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  1
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:  Neuropathy, hereditary motor and sensory, 6A (HMSN6A) [MIM:601152]: An autosomal dominant neurologic disorder characterized by optic atrophy and peripheral sensorimotor neuropathy manifesting as axonal Charcot-Marie-Tooth disease. Charcot-Marie-Tooth disease is 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. It is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies and primary peripheral axonal neuropathies. Peripheral axonal neuropathies are characterized by signs of axonal regeneration in the absence of obvious myelin alterations, and normal or slightly reduced nerve conduction velocities. {ECO:0000269|PubMed:16437557, ECO:0000269|PubMed:20350294, ECO:0000269|PubMed:24604904, ECO:0000269|PubMed:26085578}. 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.

Involvement in disease:  Charcot-Marie-Tooth disease 2A2B (CMT2A2B) [MIM:617087]: An 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. CMT2A2B is a severe form with autosomal recessive inheritance. {ECO:0000269|PubMed:18458227, ECO:0000269|PubMed:20350294, ECO:0000269|PubMed:21715711, ECO:0000269|PubMed:26085578, ECO:0000269|PubMed:26955893}. 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.

Involvement in disease:  Charcot-Marie-Tooth disease 2A2A (CMT2A2A) [MIM:609260]: An 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:15064763, ECO:0000269|PubMed:15549395, ECO:0000269|PubMed:16762064, ECO:0000269|PubMed:20350294, ECO:0000269|PubMed:22206013}. 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 CMT2A2A, CMT2A2B and HMSN6A.
Any additional useful information about the variant.

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



Sequence information

Variant position:  94
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  757
The length of the canonical sequence.

Location on the sequence:   QVLDVKGYLSKVRGISEVLA  R RHMKVAFFGRTSNGKSTVIN
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                         QVLDVKGYLSKVRGISEVLARRHMKVAFFGRTSNGKSTVIN

Mouse                         QVLDVKGYLSKVRGISEVLARRHMKVAFFGRTSNGKSTVIN

Rat                           QVLDVKGYLSKVRGISEVLARRHMKVAFFGRTSNGKSTVIN

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 – 757 Mitofusin-2
Topological domain 1 – 604 Cytoplasmic
Domain 93 – 342 Dynamin-type G
Region 30 – 94 Part of a helix bundle domain, formed by helices from N-terminal and C-terminal regions
Modified residue 111 – 111 Phosphothreonine; by PINK1
Alternative sequence 1 – 302 Missing. In isoform 2.
Mutagenesis 109 – 109 K -> AT. Does not affect its ability to cluster mitochondria; when overexpressed.
Mutagenesis 110 – 110 S -> N. Does not affect its ability to cluster mitochondria; when overexpressed.
Mutagenesis 111 – 111 T -> A. Diminishes interaction with PRKN in presence of PINK1. Abolishes phosphorylation by PINK1 and interaction with PRKN in presence of PINK1; when associated with ALA-442.
Mutagenesis 111 – 111 T -> E. Interacts with PRKN in absence of PINK1; when associated with GLU-442.


Literature citations

Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A.
Zuechner S.; Mersiyanova I.V.; Muglia M.; Bissar-Tadmouri N.; Rochelle J.; Dadali E.L.; Zappia M.; Nelis E.; Patitucci A.; Senderek J.; Parman Y.; Evgrafov O.; Jonghe P.D.; Takahashi Y.; Tsuji S.; Pericak-Vance M.A.; Quattrone A.; Battaloglu E.; Polyakov A.V.; Timmerman V.; Schroeder J.M.; Vance J.M.;
Nat. Genet. 36:449-451(2004)
Cited for: DISEASE; VARIANTS CMT2A2A PHE-69; PRO-76; GLN-94; ALA-251; HIS-280 AND SER-740;

MFN2 point mutations occur in 3.4% of Charcot-Marie-Tooth families. An investigation of 232 Norwegian CMT families.
Braathen G.J.; Sand J.C.; Lobato A.; Hoeyer H.; Russell M.B.;
BMC Med. Genet. 11:48-48(2010)
Cited for: VARIANT HMSN6A TRP-94; VARIANT CMT2A2B GLN-94; VARIANTS HIS-468; SER-570; ILE-705 AND THR-716; VARIANT CMT2A2A TRP-707;

Application of whole exome sequencing in undiagnosed inherited polyneuropathies.
Klein C.J.; Middha S.; Duan X.; Wu Y.; Litchy W.J.; Gu W.; Dyck P.J.; Gavrilova R.H.; Smith D.I.; Kocher J.P.; Dyck P.J.;
J. Neurol. Neurosurg. Psych. 85:1265-1272(2014)
Cited for: VARIANT HMSN6A GLN-94;

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.