UniProtKB/Swiss-Prot P01112: Variant p.Gly12Ser

GTPase HRas
Gene: HRAS
Chromosomal location: 11p15.5
Variant information

Variant position:  12
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 have been found in patients and disease-association is reported in literature. However, this classification is not a definitive assessment of variant pathogenicity.
  • Polymorphism: No disease-association has been reported.
  • Unclassified: Variants have been found in patients but disease-association remains unclear.

Residue change:  From Glycine (G) to Serine (S) at position 12 (G12S, p.Gly12Ser).
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 glycine (G) to small size and polar (S)
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  0
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:  Congenital myopathy with excess of muscle spindles (CMEMS) [MIM:218040]: Variant of Costello syndrome. {ECO:0000269|PubMed:17412879}. 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:  Costello syndrome (CSTLO) [MIM:218040]: A rare condition characterized by prenatally increased growth, postnatal growth deficiency, mental retardation, distinctive facial appearance, cardiovascular abnormalities (typically pulmonic stenosis, hypertrophic cardiomyopathy and/or atrial tachycardia), tumor predisposition, skin and musculoskeletal abnormalities. {ECO:0000269|PubMed:16170316, ECO:0000269|PubMed:16329078, ECO:0000269|PubMed:16443854, ECO:0000269|PubMed:17054105, ECO:0000269|PubMed:18039947, ECO:0000269|PubMed:18247425, ECO:0000269|PubMed:19995790}. 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 CSTLO and CMEMS; also found in patients with oral squamous cell carcinoma.
Any additional useful information about the variant.



Sequence information

Variant position:  12
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  189
The length of the canonical sequence.

Location on the sequence:   MTEYKLVVVGA  G GVGKSALTIQLIQNHFVDEY
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                         MTEYKLVVVGAGGVGKSALTIQLIQNHFVDEY

Mouse                         MTEYKLVVVGAGGVGKSALTIQLIQNHFVDEY

Rat                           MTEYKLVVVGAGGVGKSALTIQLIQNHFVDEY

Chicken                       MTEYKLVVVGAGGVGKSALTIQLIQNHFVDEY

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 1 – 186 GTPase HRas
Initiator methionine 1 – 1 Removed; alternate
Chain 2 – 186 GTPase HRas, N-terminally processed
Nucleotide binding 10 – 17 GTP
Modified residue 1 – 1 N-acetylmethionine; in GTPase HRas; alternate
Modified residue 2 – 2 N-acetylthreonine; in GTPase HRas, N-terminally processed
Mutagenesis 17 – 17 S -> N. Dominant negative. Prevents PLCE1 EGF-induced recruitment to plasma membrane. No effect on subcellular location of isoform 2.
Mutagenesis 26 – 26 N -> G. Loss of interaction with PLCE1; when associated with V-12.
Mutagenesis 29 – 29 V -> A. No effect on interaction with PLCE1; when associated with V-12.
Mutagenesis 32 – 32 Y -> F. Loss of interaction and recruitment to plasma membrane of PLCE1; when associated with V-12.
Beta strand 12 – 14


Literature citations

The p53 tumor-suppressor gene and ras oncogene mutations in oral squamous-cell carcinoma.
Sakai E.; Rikimaru K.; Ueda M.; Matsumoto Y.; Ishii N.; Enomoto S.; Yamamoto H.; Tsuchida N.;
Int. J. Cancer 52:867-872(1992)
Cited for: VARIANT SER-12;

Germline mutations in HRAS proto-oncogene cause Costello syndrome.
Aoki Y.; Niihori T.; Kawame H.; Kurosawa K.; Ohashi H.; Tanaka Y.; Filocamo M.; Kato K.; Suzuki Y.; Kure S.; Matsubara Y.;
Nat. Genet. 37:1038-1040(2005)
Cited for: VARIANTS CSTLO ALA-12; SER-12; VAL-12 AND ASP-13;

HRAS mutation analysis in Costello syndrome: genotype and phenotype correlation.
Gripp K.W.; Lin A.E.; Stabley D.L.; Nicholson L.; Scott C.I. Jr.; Doyle D.; Aoki Y.; Matsubara Y.; Zackai E.H.; Lapunzina P.; Gonzalez-Meneses A.; Holbrook J.; Agresta C.A.; Gonzalez I.L.; Sol-Church K.;
Am. J. Med. Genet. A 140:1-7(2006)
Cited for: VARIANTS CSTLO ALA-12; SER-12 AND CYS-13;

Genotype-phenotype correlation in Costello syndrome: HRAS mutation analysis in 43 cases.
Kerr B.; Delrue M.-A.; Sigaudy S.; Perveen R.; Marche M.; Burgelin I.; Stef M.; Tang B.; Eden O.B.; O'Sullivan J.; De Sandre-Giovannoli A.; Reardon W.; Brewer C.; Bennett C.; Quarell O.; M'Cann E.; Donnai D.; Stewart F.; Hennekam R.; Cave H.; Verloes A.; Philip N.; Lacombe D.; Levy N.; Arveiler B.; Black G.;
J. Med. Genet. 43:401-405(2006)
Cited for: VARIANTS CSTLO SER-12; CYS-12; GLU-12; ALA-12 AND ARG-117;

Diversity, parental germline origin, and phenotypic spectrum of de novo HRAS missense changes in Costello syndrome.
Zampino G.; Pantaleoni F.; Carta C.; Cobellis G.; Vasta I.; Neri C.; Pogna E.A.; De Feo E.; Delogu A.; Sarkozy A.; Atzeri F.; Selicorni A.; Rauen K.A.; Cytrynbaum C.S.; Weksberg R.; Dallapiccola B.; Ballabio A.; Gelb B.D.; Neri G.; Tartaglia M.;
Hum. Mutat. 28:265-272(2007)
Cited for: VARIANTS CSTLO SER-12 AND THR-146;

Myopathy caused by HRAS germline mutations: implications for disturbed myogenic differentiation in the presence of constitutive HRas activation.
van der Burgt I.; Kupsky W.; Stassou S.; Nadroo A.; Barroso C.; Diem A.; Kratz C.P.; Dvorsky R.; Ahmadian M.R.; Zenker M.;
J. Med. Genet. 44:459-462(2007)
Cited for: VARIANTS CMEMS VAL-12; SER-12; LYS-22 AND LYS-63;

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.