UniProtKB/Swiss-Prot P0DP23: Variant p.Asn54Ile

Calmodulin-1
Gene: CALM1
Chromosomal location: 14q24-q31
Variant information

Variant position:  54
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 Asparagine (N) to Isoleucine (I) at position 54 (N54I, p.Asn54Ile).
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 polar (N) to medium size and hydrophobic (I)
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  -3
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:  Ventricular tachycardia, catecholaminergic polymorphic, 4 (CPVT4) [MIM:614916]: An arrhythmogenic disorder characterized by stress-induced, bidirectional ventricular tachycardia that may degenerate into cardiac arrest and cause sudden death. Patients present with recurrent syncope, seizures, or sudden death after physical activity or emotional stress. CPVT4 inheritance is autosomal dominant. {ECO:0000269|PubMed:23040497}. 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 CPVT4; increased RYR2 calcium-release channel activity; not changed calcium-dependent inactivation of L-type calcium channel; not changed protein abundance; not changed structure; not changed thermal stability both in the absence and presence of calcium; no effect on the calcium binding affinity; significantly increased binding of RYR2; increased ryanodine-sensitive calcium-release channel activity; decreased of KCNN2 calcium-activated potassium channel activity; not changed KCNN2 expression; not changed KCNN2 location at membrane.
Any additional useful information about the variant.

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



Sequence information

Variant position:  54
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  149
The length of the canonical sequence.

Location on the sequence:   GTVMRSLGQNPTEAELQDMI  N EVDADGNGTIDFPEFLTMMA
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                         GTVMRSLGQNPTEAELQDMINEVDADGNGTIDFPEFLTMMA

Mouse                         GTVMRSLGQNPTEAELQDMINEVDADGNGTIDFPEFLTMMA

Rat                           GTVMRSLGQNPTEAELQDMINEVDADGNGTIDFPEFLTMMA

Xenopus laevis                GTVMRSLGQNPTEAELQDMINEVDADGNGTIDFPEFLTMMA

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 – 149 Calmodulin-1
Domain 44 – 79 EF-hand 2
Modified residue 45 – 45 Phosphothreonine; by CaMK4
Helix 46 – 56


Literature citations

Mutations in calmodulin cause ventricular tachycardia and sudden cardiac death.
Nyegaard M.; Overgaard M.T.; Sondergaard M.T.; Vranas M.; Behr E.R.; Hildebrandt L.L.; Lund J.; Hedley P.L.; Camm A.J.; Wettrell G.; Fosdal I.; Christiansen M.; Borglum A.D.;
Am. J. Hum. Genet. 91:703-712(2012)
Cited for: INVOLVEMENT IN CPVT4; VARIANTS CPVT4 ILE-54 AND SER-98; CHARACTERIZATION OF VARIANTS CPVT4 ILE-54 AND SER-98;

Distinctive malfunctions of calmodulin mutations associated with heart RyR2-mediated arrhythmic disease.
Vassilakopoulou V.; Calver B.L.; Thanassoulas A.; Beck K.; Hu H.; Buntwal L.; Smith A.; Theodoridou M.; Kashir J.; Blayney L.; Livaniou E.; Nounesis G.; Lai F.A.; Nomikos M.;
Biochim. Biophys. Acta 1850:2168-2176(2015)
Cited for: VARIANTS CPVT4 ILE-54 AND SER-98; CHARACTERIZATION OF VARIANTS CPVT4 ILE-54 AND SER-98; VARIANTS LQT14 GLY-130 AND LEU-142; CHARACTERIZATION OF VARIANTS LQT14 GLY-130 AND LEU-142; INTERACTION WITH RYR2;

Novel CPVT-Associated Calmodulin Mutation in CALM3 (CALM3-A103V) Activates Arrhythmogenic Ca Waves and Sparks.
Gomez-Hurtado N.; Boczek N.J.; Kryshtal D.O.; Johnson C.N.; Sun J.; Nitu F.R.; Cornea R.L.; Chazin W.J.; Calvert M.L.; Tester D.J.; Ackerman M.J.; Knollmann B.C.;
Circ. Arrhythm. Electrophysiol. 9:0-0(2016)
Cited for: VARIANTS CPVT4 ILE-54 AND SER-98; CHARACTERIZATION OF VARIANTS CPVT4 ILE-54; SER-98; INTERACTION WITH RYR2;

Arrhythmogenic calmodulin mutations impede activation of small-conductance calcium-activated potassium current.
Yu C.C.; Ko J.S.; Ai T.; Tsai W.C.; Chen Z.; Rubart M.; Vatta M.; Everett T.H. IV; George A.L. Jr.; Chen P.S.;
Heart Rhythm 13:1716-1723(2016)
Cited for: VARIANTS CPVT4 ILE-54 AND SER-98; CHARACTERIZATION OF VARIANTS CPVT4 ILE-54 AND SER-98; VARIANTS LQT14 LEU-90 AND GLY-130; CHARACTERIZATION OF VARIANTS LQT14 LEU-90 AND GLY-130; FUNCTION;

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.