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UniProtKB/Swiss-Prot P17661: Variant p.Ser46Phe

Desmin
Gene: DES
Chromosomal location: 2q35
Variant information

Variant position:  46
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 Serine (S) to Phenylalanine (F) at position 46 (S46F, p.Ser46Phe).
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 small size and polar (S) to large size and aromatic (F)
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:  Myopathy, myofibrillar, 1 (MFM1) [MIM:601419]: A form of myofibrillar myopathy, a group of chronic neuromuscular disorders characterized at ultrastructural level by disintegration of the sarcomeric Z disc and myofibrils, and replacement of the normal myofibrillar markings by small dense granules, or larger hyaline masses, or amorphous material. MFM1 is characterized by skeletal muscle weakness associated with cardiac conduction blocks, arrhythmias, restrictive heart failure, and accumulation of desmin-reactive deposits in cardiac and skeletal muscle cells. {ECO:0000269|PubMed:10545598, ECO:0000269|PubMed:10717012, ECO:0000269|PubMed:10905661, ECO:0000269|PubMed:11061256, ECO:0000269|PubMed:11668632, ECO:0000269|PubMed:12620971, ECO:0000269|PubMed:12766977, ECO:0000269|PubMed:14648196, ECO:0000269|PubMed:14711882, ECO:0000269|PubMed:14724127, ECO:0000269|PubMed:15495235, ECO:0000269|PubMed:15800015, ECO:0000269|PubMed:16009553, ECO:0000269|PubMed:16376610, ECO:0000269|PubMed:16865695, ECO:0000269|PubMed:17221859, ECO:0000269|PubMed:18061454, ECO:0000269|PubMed:19879535, ECO:0000269|PubMed:20829228, ECO:0000269|PubMed:22106715, ECO:0000269|PubMed:22395865, ECO:0000269|PubMed:23615443, ECO:0000269|PubMed:25394388, ECO:0000269|PubMed:27733623, ECO:0000269|PubMed:28470624, ECO:0000269|PubMed:9697706, ECO:0000269|PubMed:9736733}. Note=The disease is caused by mutations affecting the gene represented in this entry. Mutations in the DES gene are associated with a variable clinical phenotype which encompasses isolated myopathies, pure cardiac phenotypes (including dilated cardiomyopathy, restrictive cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy), cardiac conduction disease, and combinations of these disorders. If both cardiologic and neurologic features occur, they can manifest in any order, as cardiologic features can precede, occur simultaneously with, or follow manifestation of generalized neuromuscular disease (PubMed:19879535). {ECO:0000269|PubMed:19879535}.
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 MFM1; exhibits significantly delayed filament assembly kinetics when bound to NEB; enhanced binding affinity towards NEB.
Any additional useful information about the variant.

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



Sequence information

Variant position:  46
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  470
The length of the canonical sequence.

Location on the sequence:   LGSPLSSPVFPRAGFGSKGS  S SSVTSRVYQVSRTSGGAGGL
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                         LGSPLSSPVFP-RAGFGSKG-SSSSVTSRVYQVSRTSGGAGGL

                              LGSPLGSPVFP-RAGFGTKG-SSSSVTSRVYQVSRTSGGAG

Mouse                         LGSPLSSPVFP-RAGFGTKG-SSSSMTSRVYQVSRTSGGAG

Rat                           LGSPLSSPVFP-RAGFGTKG-SSSSVTSRVYQVSRTSGGAG

Pig                           LGSPLSSPVFP-RAGFGTKG-SSSSVTSRVYQVSRTSGGAG

Bovine                        LGSPLSSPVFP-RAGFGTKG-SSSSVTSRVYQVSRTSGGAG

Chicken                       -----TSPVFP-RASFGSRG-SGSSVTSRVYQVSRTSA-VP

Xenopus laevis                ------SPSFSTRSSFGSKGASSSSVSSRVYQVSRSTA-AP

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 – 470 Desmin
Region 2 – 108 Head
Modified residue 28 – 28 Phosphoserine; by CDK1
Modified residue 31 – 31 Phosphoserine
Modified residue 32 – 32 Phosphoserine; by CDK1
Modified residue 37 – 37 Asymmetric dimethylarginine; alternate
Modified residue 37 – 37 Omega-N-methylarginine; alternate
Modified residue 45 – 45 Phosphoserine
Modified residue 48 – 48 Phosphoserine
Modified residue 51 – 51 Phosphoserine
Modified residue 58 – 58 ADP-ribosylarginine
Modified residue 60 – 60 Phosphoserine; by AURKB


Literature citations

Myofibrillar myopathy: clinical, morphological and genetic studies in 63 patients.
Selcen D.; Ohno K.; Engel A.G.;
Brain 127:439-451(2004)
Cited for: VARIANTS MFM1 ILE-2; TYR-46; PHE-46 AND THR-449;

Nebulin binding impedes mutant desmin filament assembly.
Baker L.K.; Gillis D.C.; Sharma S.; Ambrus A.; Herrmann H.; Conover G.M.;
Mol. Biol. Cell 24:1918-1932(2013)
Cited for: CHARACTERIZATION OF VARIANTS MFM1 PHE-46; ASP-245 AND ILE-453; INTERACTION WITH NEB;

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.