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UniProtKB/Swiss-Prot Q15465: Variant p.Thr267Ile

Sonic hedgehog protein
Gene: SHH
Chromosomal location: 7q36
Variant information

Variant position:  267
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 Threonine (T) to Isoleucine (I) at position 267 (T267I, p.Thr267Ile).
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 (T) to medium size and hydrophobic (I)
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:  Holoprosencephaly 3 (HPE3) [MIM:142945]: A structural anomaly of the brain, in which the developing forebrain fails to correctly separate into right and left hemispheres. Holoprosencephaly is genetically heterogeneous and associated with several distinct facies and phenotypic variability. The majority of holoprosencephaly type 3 cases are apparently sporadic, although clear examples of autosomal dominant inheritance have been described. {ECO:0000269|PubMed:10441331, ECO:0000269|PubMed:10556296, ECO:0000269|PubMed:11479728, ECO:0000269|PubMed:15107988, ECO:0000269|PubMed:15221788, ECO:0000269|PubMed:15942952, ECO:0000269|PubMed:15942953, ECO:0000269|PubMed:16282375, ECO:0000269|PubMed:17001669, ECO:0000269|PubMed:19603532, ECO:0000269|PubMed:8896572, ECO:0000269|PubMed:9302262}. 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 HPE3.
Any additional useful information about the variant.



Sequence information

Variant position:  267
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  462
The length of the canonical sequence.

Location on the sequence:   GAKKVFYVIETREPRERLLL  T AAHLLFVAPHNDSATGEPEA
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                         GAKKVFYVIETREPRERLLLTAAHLLFVAPHNDSATGEPEA

Mouse                         GAKKVFYVIETLEPRERLLLTAAHLLFVAPHND--------

Rat                           GAKKVFYVIETREPRERLLLTAAHLLFVAPHND--------

Chicken                       SSRKLFYVIETRQPRARLLLTAAHLLFVAPQHNQSE-----

Xenopus laevis                DVKKLFYVIETSQRKIR--LTAAHLLFVAQTK---------

Zebrafish                     TTRRVFYVIETQEPVEKITLTAAHLLFVLDNS---------

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 24 – 462 Sonic hedgehog protein
Site 267 – 267 Involved in auto-cleavage
Site 270 – 270 Essential for auto-cleavage
Glycosylation 278 – 278 N-linked (GlcNAc...) asparagine


Literature citations

Wide phenotypic variability in families with holoprosencephaly and a sonic hedgehog mutation.
Hehr U.; Gross C.; Diebold U.; Wahl D.; Beudt U.; Heidemann P.; Hehr A.; Mueller D.;
Eur. J. Pediatr. 163:347-352(2004)
Cited for: VARIANTS HPE3 ALA-27; ILE-267 AND THR-373;

The mutational spectrum of holoprosencephaly-associated changes within the SHH gene in humans predicts loss-of-function through either key structural alterations of the ligand or its altered synthesis.
Roessler E.; El-Jaick K.B.; Dubourg C.; Velez J.I.; Solomon B.D.; Pineda-Alvarez D.E.; Lacbawan F.; Zhou N.; Ouspenskaia M.; Paulussen A.; Smeets H.J.; Hehr U.; Bendavid C.; Bale S.; Odent S.; David V.; Muenke M.;
Hum. Mutat. 30:E921-E935(2009)
Cited for: VARIANTS HPE3 THR-6; PRO-17; LEU-26; ALA-27; ARG-31; PRO-39; LYS-53; VAL-83; PHE-84; VAL-88; HIS-100; ARG-102; TYR-102; 106-LEU-ASN-107 DEL; PHE-109; THR-110; ASP-110; PHE-111; ASN-111; LYS-115; GLY-117; ARG-117; MET-124; LYS-136; PRO-140; GLN-140; ASP-143; PRO-144; ASN-147; ARG-150; LYS-150; ARG-156; CYS-170; HIS-171; 176-GLU--LYS-178 DEL; ARG-183; PHE-183; TYR-183; LEU-184; GLN-188; GLU-196; 196-GLY--PRO-200 DEL; VAL-197; SER-198; PHE-198; PRO-218; ASN-222; GLU-224; THR-226; VAL-231; GLY-232; PRO-234; ARG-236; ASN-236; VAL-241; LEU-241; ASN-255; 263-ARG--ALA-269 DEL; ILE-267; PRO-271; GLU-275; TRP-280; ASP-290; ALA-296; CYS-310; SER-321; ALA-332; VAL-346; ARG-347; GLN-347; LEU-347; THR-354; LEU-362; TYR-363; CYS-364; THR-373; ARG-374; ASP-376; SER-377; 378-ALA--PHE-380 DEL; PRO-381; PRO-382; THR-383; THR-391; 402-GLY--GLY-409 DEL; 405-ASP--GLY-409 DEL; GLY-411 INS; ALA-416; ALA-424; ASN-435; LEU-436 AND ARG-456;

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.