Default scores were based on the following information for all the parameters. User can modify the scores for default sites and can also
add any number of new sites if required in the available text areas in the format shown. Each site should be separated by a space.
The format should be read as follows:G4580A#5: G to A base change at position 4580 is assigned a default score of 5.
For any Polymorphism, score =1. The score increases for every parameter and the increment depends on the impact of the parameter.
Links to OMIM and SWISSPROT provided for all genes alongside.
Go to Index Page
SIFT   Sorting Intolerant From Tolerant
  Given a protein sequence, SIFT will return predictions for what amino acid substitutions will affect protein function
  SIFT is a multistep procedure that:
  (1) searches for and chooses similar sequences
  (2) makes an alignment of these sequences
  (3) calculates scores based on the amino acids appearing at each position in the alignment.
    For more information click -> http://blocks.fhcrc.org/sift/SIFT.html
PolyPhen   Polymorphism Phenotyping
  This tool predicts possible impact of an amino acid substitution on the structure & function of a human protein using
  straightforward physical and comparative considerations. This prediction is based on straightforward empirical rules 
  which are applied to the sequence, phylogenetic and structural information characterizing the substitution.
  PolyPhen uses empirically derived rules to predict that an nsSNP is
  (1) probably damaging, i.e., it is with high confidence supposed to affect protein function or structure
  (2) possibly damaging, i.e., it is supposed to affect protein function or structure
  (3) benign, most likely lacking any phenotypic effect
  (4) unknown, when in some rare cases, the lack of data do not allow PolyPhen to make a prediction
    For more information click -> http://www.bork.embl-heidelberg.de/PolyPhen/
PLHOST Invariant
 
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HRE   The human and rodent mitochondrial genomes contain nucleotide sequences similar to both type of type I & type II HREs
  The steroid and thyroid hormone effects on the mitochondrial genes are direct, concomitant with the effects on nuclear
  genes and involving similar molecular mechanisms to those mediating steroid-thyroid hormone actions on nuclear gene
  transcription (Steroid 61:226-232, 1996). Sequences showing partial similarity to the GRE consensus sequence
  detected in the human mitochondrial genome are as follows:
  1196       AGAGGA NNN TGTTCT     1210
  3218       AGAACA NNN TTTGTT      3232
  4103       TAACCT NNN TGTTCT      4117
    16494     CCGACA NNN GGTTCC   16508
Frequency   Frequency of mutation should be significantly high in patients as compared to normal individuals. If a particular
of Mutation mutation appears more often as polymorphism in normal individuals then it should be given a negative score.
    Sites having similar frequencies in both are not informative and hence are not scored.
HSP & LSP   Heavy Strand Promoter & Light Strand Promoter
  Mammalian mitochondrial genome contains only 2 promoters : LSP & HSP, which produce near-genomic length
  transcripts after that RNA processing release individual mRNAs, tRNAs and rRNAs (Ojala et al. 1981; Clayton, 1991).
  Transcription from LSP is necessary not only for gene expression but also for production of RNA primers required for
  initiation of mtDNA replication (Shadel & Clayton, 1997) [EMBO Journal 2004, 23:4606-4614].
  POLMRT recognize promoter elements in a sequence-specific manner. Any mutation causing a base change can change
  this interaction effect mtDNA transcription rate. Hence mutations in LSP and HSP are given default high scores. Score
    for LSP is higher because it plays dual role in mtDNA replication and transcription
12SRNA   12 S Ribosomal RNA
  1095T-C: mutation is to destroy the stem-loop secondary structure, resulting in impaired translation
    (Thyagarajan, D:Ann. Neurology 48::730-736,2000)
16SRNA
Complex I ND1-6, ND4L Generate NAD used in the TCA cycle for conversion of Fumarate to OAA and gives lone pair of electron
  (from NADH) to the ETC
  Complex I can be subdivided into 3 main fractions: the flavoprotein fragment, the iron-protein fragment,
  and the hydrophobic protein fragment
  Of the 7 mitochondrial DNA Complex I genes, the gene products for MTND1, MTND3, and MTND4L
  have been localized to the hydrophobic protein fragment (Ragan, 1987), and the MTND2, MTND4, and MTND5
  gene products probably reside there also.
  The hydrophobic protein fragment contains the iron-sulfur centers that are the likely electron donors to
  ubiquinone (Ohnishi et al., 1985; Ohnishi et al., 1974).
  The 3644T-C mutation in ND1 converts amino acid 113, valine, to alanine. Munakata et al. (2004) noted that
    val113 is well conserved from Drosophila to mammalian species
Complex III CYTB CYTB catalyzes the transfer of electrons from ubiquinol (reduced Coenzyme Q10) to cytochrome c and utilizes the
  energy to translocate protons from inside the mitochondrial inner membrane to outside.
  These 11 complex III subunits include core proteins I and II, cytochrome b (subunit III), cytochrome c1 (subunit IV),
  the Rieske iron-sulfur protein (subunit V), and several smaller polypeptides.
  MTCYB is a highly evolutionarily conserved, hydrophobic protein containing 8 or 9 transmembrane domains
  and 2 heme groups
  The patient was found to have a 14849T-C mutation in the MTCYB gene, resulting in a substitution of a
     highly conserved serine for proline at position 35.
Complex IV   Complex IV is located within the mitochondrial inner membrane and is the third and final enzyme of the ETC
  It collects electrons from reduced cytochrome c and transfers them to oxygen to give water.
  Complex IV is composed of 13 polypeptides: 3mtEncoded and others nuclear DNA encoded
   
  COX 1 In mitochondrial Complex IV, the 2 hemes are a and a3 and the 2 coppers are CuA and CuB. The 2 hemes and CuB
  are bound to subunit I. For mammalian MTCO1, there are 12 membrane-spanning alpha-helices (I to XII). 
  Of these helices, heme a is located between helix II and X, ligated with the invariant histidines at amino acid
   102 (MTCO1 88) of helix II and at 421 (MTCO1 378) of helix X. Helix X lies between heme a and heme a3,
  with heme a3 bound to the opposite side of helix X at invariant histidine at amino acid 419 (MTCO1 376).
   Heme a3 is a component of a binuclear center which includes CuB and where oxygen is reduced to water.
  CuB is thought to lie adjacent to the iron of heme a3 and to be ligated to helix VI through invariant histidine
   284 (MTCO1 240) and to helix VII through invariant histidines 333 and 334 (MTCO1 290 and 291).
  Amino acids histidine 411 (MTCO1 368), aspartate 412 (369), threonine 413 (370), and tyrosine 414 (371)
   occur in the conserved loop between helices IX and X, lying close to hemes a and a3, and may be in the proximity
   of the CuA located in subunit II (Hosler et al., 1993).
  Jaksch et al. (1998) identified a G-to-A transition at nucleotide 6480 of the MTCO1 gene in a child, her mother, 
  and sister with cytochrome c oxidase deficiency (220110) associated with sensorineural hearing loss, ataxia,
  myoclonic epilepsy, and mental retardation.
   
  COX 2 It collects electrons from ferrocytochrome c (reduced cytochrome c) and transfers them to oxygen to give water.
  Subunit II of Complex IV interacts with cytochrome c and contains the CuA center. This means that the pathway
   of electron transfer through Complex IV is from cytochrome c, to CuA, to cytochrome a, and then to the binuclear
    center of cytochrome a3-CuB. It is thought that the transfer of electrons from cytochrome a to the binuclear center
   is the key control point in the reaction and one of the major points of energy transduction (Hill, 1993).
  CuA most likely resides in a loop containing conserved cysteines at amino acids 196 and 200 and a conserved
   histidine at 204, with the fourth ligand being histidine 161
  Cytochrome c interacts with subunit II through the association of a ring of lysines around the heme edge of
  cytochrome c with carboxyls in subunit II, specifically glutamate 129, aspartate 132, and glutamate 198
   (Hill, 1993; Capaldi, 1990).
  The 25-np 3-prime-nontranslated sequence (5-prime-CACCCCCTCTACCCCCTCTAGAGGG) contains 2 9-np repeats
  which are polymorphic in the world populations. One polymorphism involves the deletion of 1 repeat and is common
   in Asian, Polynesian and Native American mtDNAs. A second polymorphism involves additional Cs' inserted within
  the runs of Cs (Cann and Wilson, 1983; Wrischnik et al., 1987; Hertzberg et al., 1989; Ballinger et al., 1992;
  Schurr et al., 1990; Torroni et al., 1992; Torroni et al., 1993).
   
  COX 3 Subunit III is a highly conserved and ubiquitous subunit of Complex III, yet its function remains unclear
  Cleavage at the 5-prime end occurs between the two As of the MTATP6 termination codon ACA TA //A UG ACC
   (ThrTerMetThr) creating transcript 15, the MTCO3 mRNA (Montoya et al., 1981; Ojala et al., 1981;
   Attardi et al., 1982). This is the only instance in which 2 separate transcripts, transcript 14  for MTATP8-MTATP6
   and transcript 15 for MTCO3, are not separated by a tRNA. Hence, they must be processed by a separate system.
  If the 14+15 transcript were not cleaved, then MTATP6 would be translated, but MTCO3 might not be translated
  since its initiation codon overlaps the MTATP6 termination codon. Since the ratio between MTATP6 and MTCO3
  can vary between patient and control cell mitochondria, it is possible that the cleavage of transcript 14 + 15
  provides a mechanism for modulating the biogenesis of the electron transport chain relative to the ATP synthase
    (Wallace et al., 1986).
   
Complex V ATP6 In an isolated case of mental retardation and ataxia without retinitis pigmentosa, de Coo et al. (1996) found an
  8993T-G transversion (516060.0001).
  Holt et al. (1990) found a heteroplasmic T-to-G transversion at nucleotide pair 8993 in a maternal pedigree which
  resulted in the change of a hydrophobic leucine to a hydrophilic arginine at position 156 in subunit 6  of
  mitochondrial H(+)-ATPase. The clinical symptoms varied in proportion to the percentage of mutant mtDNAs
   but the most common clinical presentation included neurogenic muscle weakness, ataxia, and retinitis
   pigmentosa, leading to the designation of NARP syndrome (551500).
   The insertion of an arginine in the hydrophobic sequence of ATPase 6 probably interferes with the hydrogen ion
   channel formed by subunits 6 and 9 of the ATPase, thus causing failure of ATP synthesis.
  8993T-G is a well known and established mutation for ataxia cases
   
  ATP8  
tRNA   Transfer RNA
  The default sites shown for each tRNA were scored because they were either reported to cause ataxia or lie at conserved
  sites in the tRNA. The literature for each site is presented below.
   
tRNA-Ala OMIM:590000 G5650A#7 :  J. Med. Genet. 40: 752-757, 2003
tRNA-Arg OMIM:590005 X
tRNA-Asn OMIM:590010 G5703A#5 : J. Clin. Invest. 92: 2906-2915, 1993
tRNA-Asp OMIM:590015 A7526G#5 : Am. J. Med. Genet. 137A: 170-175, 2005
tRNA-Cys OMIM:590020 X
tRNA-Gln OMIM:590030 X
tRNA-Glu OMIM:590025 T14709C#6 : Am. J. Hum. Genet. 56: 1026-1033, 1995
tRNA-Gly OMIM:590035 T9997C#8 : Am. J. Hum. Genet. 55: 437-446, 1994
    T10010C#0 : Neurology 58: 1282-1285, 2002
    A10044G#8 : J. Biol. Chem. 278: 16828-16833, 2003
tRNA-His OMIM:590040 G12192A#3 : . J. Hum. Genet. 67: 1617-1620, 2000
    G12183A#7 : Neurology 60: 1200-1203, 2003
    G12147A#9 : Arch. Neurol. 61: 269-272, 2004; Neurology 62: 1420-1423, 2004
tRNA-Ile OMIM:590045 A4317G#0 : J. Biol. Chem. 278: 16828-16833, 2003
    A4269G#0: Biochem. Biophys. Res. Commun. 186: 47-53, 1992
    G4284A#5 : Ann. Neurol. 51: 118-122, 2002
    G4300A#3 : J. Am. Coll. Cardiol. 41: 1786-1796, 2003
tRNA-Leu OMIM:590050 A3243G#4 : Nature 348: 651-653, 1990; Biochem. Biophys. Res. Commun. 173: 816-822, 1990
    T3271C#4 : Biochim. Biophys. Acta 1097: 238-240, 1991
    C3256T#3 : J. Clin. Invest. 92: 2906-2915, 1993
    C3303T#5 : Hum. Mutat. 3: 37-43, 1994
    T3252C#2 : Hum. Molec. Genet. 2: 2081-2087, 1993
    A3251G#3 : Quart. J. Med. 86: 709-713, 1993
    A3260G#1 :  J. Clin. Invest. 93: 1102-1107, 1994
    T3250C#3 : J. Pediat. 130: 138-145, 1997
    T3290C#2 : Acta Paediat. 88: 957-960, 1999
    A3274G#1 : Neurology 57: 1930-1931, 2001 (not in white blood cells )
    G3249A#1 : Arch. Neurol. 58: 1113-1118, 2001
tRNA-Leu2 OMIM:590055 A12320G#5 : Am. J. Hum. Genet. 60: 373-380, 1997 (mutation present only in skeletal muscle)
    T12297C#6 : Europ. J. Hum. Genet. 9: 311-315, 2001
tRNA-Lys OMIM:590060 A8344G#9 : Muscle Nerve 17: 52-57, 1994 (This is one of the reference that associates this site with ataxia)
    T8356C#7 : Am. J. Hum. Genet. 51: 1213-1217, 1992
    G8363A#6 : Am. J. Hum. Genet. 58: 933-939, 1996
    G8313A#7 : Pediat. Res. 42: 448-454, 1997
    G8361A#3 : Biochem. Biophys. Res. Commun. 245: 523-527, 1998
tRNA-Met OMIM:590065 X
tRNA-Phe OMIM:590070 G583A#8 : J. Neurol. Neurosurg. Psychiat. 65: 512-517, 1998
tRNA-Pro OMIM:590075 G15990A#3 : Nature Genet. 4: 284-288, 1993 (not detected in WBC)
    T15965C#1 : Neurogenetics 2: 121-127, 1999 (histologically proven idiopathic Parkinson disease )
tRNA-Ser OMIM:590080 T7512C#6 : Biochem. Biophys. Res. Commun. 214: 86-93, 1995; J. Med. Genet. 35: 895-900, 1998
    A7445G#8 : Molec. Cell. Biol. 18: 5868-5879, 1998
    X7472C#3 : Hum. Molec. Genet. 4: 1421-1427, 1995; J. Med. Genet. 35: 895-900, 1998
    T7510C#5 : J. Med. Genet. 37: 692-694, 2000
tRNA-Ser2 OMIM:590085 C12258A#7 : Am. J. Hum. Genet. 64: 971-985, 1999
tRNA-Thr OMIM:590090 G15950A#1 : Neurogenetics 2: 121-127, 1999
tRNA-Trp OMIM:590095 G5549A#7 : Ann. Neurol. 37: 400-403, 1995
    X5537T#4 : Neuropediatrics 34: 87-91, 2003; Ann. Neurol. 42: 256-260, 1997
    G5521A#2 : Neuromusc. Disord. 8: 291-295, 1998 (not detected in leukocytes)
tRNA-Tyr OMIM:590100 A5874G#4 : Neurology 55: 1210-1212, 2000
    X5885T#6 : Neurology 57: 2298-2301, 2001
    G5877A#5 : J. Med. Genet. 38: 703-705, 2001
    A5843G#5 : Am. J. Med. Genet. 123A: 172-178, 2003
tRNA-Val OMIM:590105 G1606A#9 : Ann. Neurol. 43: 98-101, 1998; . Neurol. 59: 1013-1015, 2002
    C1624T#7 : Nature Genet. 30: 145-146, 2002