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UniProtKB/Swiss-Prot Q6V0I7: Variant p.Glu2375Lys

Protocadherin Fat 4
Gene: FAT4
Variant information

Variant position:  2375
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 Glutamate (E) to Lysine (K) at position 2375 (E2375K, p.Glu2375Lys).
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 acidic (E) to large size and basic (K)
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:  Van Maldergem syndrome 2 (VMLDS2) [MIM:615546]: An autosomal recessive disorder characterized by intellectual disability, typical craniofacial features, auditory malformations resulting in hearing loss, and skeletal and limb malformations. Some patients have renal hypoplasia. Brain MRI typically shows periventricular nodular heterotopia. {ECO:0000269|PubMed:24056717}. 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:  Hennekam lymphangiectasia-lymphedema syndrome 2 (HKLLS2) [MIM:616006]: A form of Hennekam lymphangiectasia-lymphedema syndrome, a generalized lymph-vessels dysplasia characterized by intestinal lymphangiectasia with severe lymphedema of the limbs, genitalia and face. In addition, affected individuals have unusual facies and some manifest mental retardation. HKLLS2 individuals have lymphangiectasia variably affecting the gut, pericardium, lungs, kidneys, and genitalia. Other features include camptodactyly and rare syndactyly. HKLLS2 inheritance is autosomal recessive. {ECO:0000269|PubMed:24913602}. 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 VMLDS2 and HKLLS2.
Any additional useful information about the variant.

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



Sequence information

Variant position:  2375
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  4981
The length of the canonical sequence.

Location on the sequence:   DDVNDNVPTFASKAYFTTIP  E DAPTGTDVLLVNASDADASK
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                         DDVNDNVPTFASKAYFTTIPEDAPTGTDVLLVNASDADASK

Mouse                         DDINDNVPTFANNMYLTSIAEDARTGTDVLLVNASDADAAA

Caenorhabditis elegans        -----------------------------------------

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 39 – 4981 Protocadherin Fat 4
Topological domain 39 – 4504 Extracellular
Domain 2365 – 2466 Cadherin 23
Glycosylation 2387 – 2387 N-linked (GlcNAc...) asparagine


Literature citations

Mutations in genes encoding the cadherin receptor-ligand pair DCHS1 and FAT4 disrupt cerebral cortical development.
Cappello S.; Gray M.J.; Badouel C.; Lange S.; Einsiedler M.; Srour M.; Chitayat D.; Hamdan F.F.; Jenkins Z.A.; Morgan T.; Preitner N.; Uster T.; Thomas J.; Shannon P.; Morrison V.; Di Donato N.; Van Maldergem L.; Neuhann T.; Newbury-Ecob R.; Swinkells M.; Terhal P.; Wilson L.C.; Zwijnenburg P.J.; Sutherland-Smith A.J.; Black M.A.; Markie D.; Michaud J.L.; Simpson M.A.; Mansour S.; McNeill H.; Goetz M.; Robertson S.P.;
Nat. Genet. 45:1300-1308(2013)
Cited for: DEVELOPMENTAL STAGE; VARIANTS VMLDS2 LYS-2375; PHE-4159 AND TYR-4398;

Hennekam syndrome can be caused by FAT4 mutations and be allelic to Van Maldergem syndrome.
Alders M.; Al-Gazali L.; Cordeiro I.; Dallapiccola B.; Garavelli L.; Tuysuz B.; Salehi F.; Haagmans M.A.; Mook O.R.; Majoie C.B.; Mannens M.M.; Hennekam R.C.;
Hum. Genet. 133:1161-1167(2014)
Cited for: INVOLVEMENT IN HKLLS2; VARIANTS HKLLS2 LEU-475; GLN-486; LYS-2375 AND PHE-4282;

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.