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UniProtKB/Swiss-Prot P98164: Variant p.Tyr2522His

Low-density lipoprotein receptor-related protein 2
Gene: LRP2
Variant information

Variant position:  2522
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 Tyrosine (Y) to Histidine (H) at position 2522 (Y2522H, p.Tyr2522His).
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 aromatic (Y) to medium size and polar (H)
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:  Donnai-Barrow syndrome (DBS) [MIM:222448]: Rare autosomal recessive disorder characterized by major malformations including agenesis of the corpus callosum, congenital diaphragmatic hernia, facial dysmorphology, ocular anomalies, sensorineural hearing loss and developmental delay. The FOAR syndrome was first described as comprising facial anomalies, ocular anomalies, sensorineural hearing loss, and proteinuria. DBS and FOAR were first described as distinct disorders but the classic distinguishing features between the 2 disorders were presence of proteinuria and absence of diaphragmatic hernia and corpus callosum anomalies in FOAR. Early reports noted that the 2 disorders shared many phenotypic features and may be identical. Although there is variability in the expression of some features (e.g., agenesis of the corpus callosum and proteinuria), DBS and FOAR are now considered to represent the same entity. {ECO:0000269|PubMed:17632512}. 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 DBS.
Any additional useful information about the variant.

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



Sequence information

Variant position:  2522
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  4655
The length of the canonical sequence.

Location on the sequence:   VIARVPKPRAIVLDPCQGYL  Y WADWDTHAKIERATLGGNFR
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                         VIARVPKPRAIVLDPCQGYLYWADWDTHAKIERATLGGNFR

Mouse                         VIARVSKPRAIVLDPCRGYMYWTDWGTNAKIERATLGGNFR

Rat                           VIARVSKPRAIVLDPCRGYMYWTDWGTNAKIERATLGGNFR

Pig                           VVARVTKPRAIVLDPCQGYMYWTDWSTNAQIERATMAGNFR

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 26 – 4655 Low-density lipoprotein receptor-related protein 2
Topological domain 26 – 4423 Extracellular
Repeat 2519 – 2562 LDL-receptor class B 25


Literature citations

Mutations in LRP2, which encodes the multiligand receptor megalin, cause Donnai-Barrow and facio-oculo-acoustico-renal syndromes.
Kantarci S.; Al-Gazali L.; Hill R.S.; Donnai D.; Black G.C.M.; Bieth E.; Chassaing N.; Lacombe D.; Devriendt K.; Teebi A.; Loscertales M.; Robson C.; Liu T.; MacLaughlin D.T.; Noonan K.M.; Russell M.K.; Walsh C.A.; Donahoe P.K.; Pober B.R.;
Nat. Genet. 39:957-959(2007)
Cited for: VARIANT DBS HIS-2522;

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.