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UniProtKB/Swiss-Prot P17612: Variant p.Leu206Arg

cAMP-dependent protein kinase catalytic subunit alpha
Gene: PRKACA
Variant information

Variant position:  206
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 Leucine (L) to Arginine (R) at position 206 (L206R, p.Leu206Arg).
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 hydrophobic (L) to large size and basic (R)
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:  Primary pigmented nodular adrenocortical disease 4 (PPNAD4) [MIM:615830]: A rare bilateral adrenal defect causing ACTH-independent Cushing syndrome. Macroscopic appearance of the adrenals is characteristic with small pigmented micronodules observed in the cortex. Adrenal glands show overall normal size and weight, and multiple small yellow-to-dark brown nodules surrounded by a cortex with a uniform appearance. Microscopically, there are moderate diffuse cortical hyperplasia with mostly nonpigmented nodules, multiple capsular deficits and massive circumscribed and infiltrating extra-adrenal cortical excrescences with micronodules. Clinical manifestations of Cushing syndrome include facial and truncal obesity, abdominal striae, muscular weakness, osteoporosis, arterial hypertension, diabetes. {ECO:0000269|PubMed:24571724, ECO:0000269|PubMed:24700472, ECO:0000269|PubMed:24747643, ECO:0000269|PubMed:24855271}. 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 PPNAD4; somatic mutation; the mutation results in cAMP-independent basal protein kinase activity and constitutive activation of protein kinase A.
Any additional useful information about the variant.

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



Sequence information

Variant position:  206
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  351
The length of the canonical sequence.

Location on the sequence:   FGFAKRVKGRTWTLCGTPEY  L APEIILSKGYNKAVDWWALG
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                         FGFAKRVKGRTWTLCGTPEYLAPEIILSKGYNKAVDWWALG

                              FGFAKRVKGRTWTLCGTPEYLAPEIILSKGYNKAVDWWALG

Mouse                         FGFAKRVKGRTWTLCGTPEYLAPEIILSKGYNKAVDWWALG

Rat                           FGFAKRVKGRTWTLCGTPEYLAPEIILSKGYNKAVDWWALG

Pig                           FGFAKRVKGRTWTLCGTPEYLAPEIILSKGYNKAVDWWALG

Bovine                        FGFAKRVKGRTWTLCGTPEYLAPEIILSKGYNKAVDWWALG

Sheep                         FGFAKRVKGRTWTLCGTPEYLAPEIILSKGYNKAVDWWALG

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 – 351 cAMP-dependent protein kinase catalytic subunit alpha
Domain 44 – 298 Protein kinase
Modified residue 196 – 196 Phosphothreonine
Modified residue 198 – 198 Phosphothreonine; by PDPK1
Mutagenesis 195 – 195 R -> A. No phosphorylation.
Mutagenesis 201 – 201 G -> A. No phosphorylation.
Mutagenesis 202 – 202 T -> A. No phosphorylation.
Mutagenesis 205 – 205 Y -> A. Loss of allosteric regulation.


Literature citations

Recurrent activating mutation in PRKACA in cortisol-producing adrenal tumors.
Goh G.; Scholl U.I.; Healy J.M.; Choi M.; Prasad M.L.; Nelson-Williams C.; Kunstman J.W.; Kuntsman J.W.; Korah R.; Suttorp A.C.; Dietrich D.; Haase M.; Willenberg H.S.; Staalberg P.; Hellman P.; Akerstroem G.; Bjoerklund P.; Carling T.; Lifton R.P.;
Nat. Genet. 46:613-617(2014)
Cited for: INVOLVEMENT IN PPNAD4; VARIANT PPNAD4 ARG-206; CHARACTERIZATION OF VARIANT PPNAD4 ARG-206;

Constitutive activation of PKA catalytic subunit in adrenal Cushing's syndrome.
Beuschlein F.; Fassnacht M.; Assie G.; Calebiro D.; Stratakis C.A.; Osswald A.; Ronchi C.L.; Wieland T.; Sbiera S.; Faucz F.R.; Schaak K.; Schmittfull A.; Schwarzmayr T.; Barreau O.; Vezzosi D.; Rizk-Rabin M.; Zabel U.; Szarek E.; Salpea P.; Forlino A.; Vetro A.; Zuffardi O.; Kisker C.; Diener S.; Meitinger T.; Lohse M.J.; Reincke M.; Bertherat J.; Strom T.M.; Allolio B.;
N. Engl. J. Med. 370:1019-1028(2014)
Cited for: VARIANT PPNAD4 ARG-206; CHARACTERIZATION OF VARIANT PPNAD4 ARG-206;

Activating hotspot L205R mutation in PRKACA and adrenal Cushing's syndrome.
Cao Y.; He M.; Gao Z.; Peng Y.; Li Y.; Li L.; Zhou W.; Li X.; Zhong X.; Lei Y.; Su T.; Wang H.; Jiang Y.; Yang L.; Wei W.; Yang X.; Jiang X.; Liu L.; He J.; Ye J.; Wei Q.; Li Y.; Wang W.; Wang J.; Ning G.;
Science 344:913-917(2014)
Cited for: VARIANT PPNAD4 ARG-206; CHARACTERIZATION OF VARIANT PPNAD4 ARG-206;

Recurrent somatic mutations underlie corticotropin-independent Cushing's syndrome.
Sato Y.; Maekawa S.; Ishii R.; Sanada M.; Morikawa T.; Shiraishi Y.; Yoshida K.; Nagata Y.; Sato-Otsubo A.; Yoshizato T.; Suzuki H.; Shiozawa Y.; Kataoka K.; Kon A.; Aoki K.; Chiba K.; Tanaka H.; Kume H.; Miyano S.; Fukayama M.; Nureki O.; Homma Y.; Ogawa S.;
Science 344:917-920(2014)
Cited for: VARIANT PPNAD4 ARG-206; CHARACTERIZATION OF VARIANT PPNAD4 ARG-206;

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.