UniProtKB/Swiss-Prot P49768: Variant p.Gly206Asp

• Variant information
• Sequence information
• Literature citations
• All

Variant information

Variant position: 206 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Type of variant: LP/P [Disclaimer: Variants classification is intended for research purposes only, not for clinical and diagnostic use. The label disease variant is assigned according to literature reports on probable disease-association that can be based on theoretical reasons. This label must not be considered as a definitive proof for the pathogenic role of a variant.] The variants are classified into three categories: LP/P, LB/B and US.

• LP/P: likely pathogenic or pathogenic.
• LB/B: likely benign or benign.
• US: uncertain significance

Residue change: From Glycine (G) to Aspartate (D) at position 206 (G206D, p.Gly206Asp). 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 medium size and acidic (D) 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
Variant description: In AD3; affects APP processing resulting in increased amyloid-beta 42/amyloid-beta 40 ratio; does not affect NOTCH processing; does not affect endoproteolysis; reduced interaction with PEN2; results in decreased protein levels in the endoplasmic reticulum but increased levels in early endosome; reduced ability to maintain ER calcium homeostasis. Any additional useful information about the variant.
Other resources: Links to websites of interest for the variant.

• Variant rs63750082 [ dbSNP | Ensembl ]

Sequence information

Variant position: 206 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Protein sequence length: 467 The length of the canonical sequence.
Location on the sequence: FKTYNVAVDYITVALLIWNF G VVGMISIHWKGPLRLQQAYL 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.
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.

Type	Positions	Description
Chain	1 – 298	Presenilin-1 NTF subunit
Transmembrane	195 – 216	Helical
Alternative sequence	185 – 467	Missing. In isoform 4.
Mutagenesis	202 – 202	I -> F. Nearly abolishes protease activity with APP.
Mutagenesis	212 – 212	S -> Y. Nearly abolishes protease activity with APP.
Mutagenesis	214 – 214	H -> D. Nearly abolishes protease activity with APP. Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro.
Mutagenesis	219 – 219	L -> F. Decreased protease activity with APP. Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro.
Mutagenesis	223 – 223	Q -> R. Abolishes protease activity with APP.
Mutagenesis	226 – 226	L -> F. Increases protease activity with APP.
Helix	195 – 214

Literature citations

G206D mutation of presenilin-1 reduces Pen2 interaction, increases Abeta42/Abeta40 ratio and elevates ER Ca(2+) accumulation.
Chen W.T.; Hsieh Y.F.; Huang Y.J.; Lin C.C.; Lin Y.T.; Liu Y.C.; Lien C.C.; Cheng I.H.;
Mol. Neurobiol. 52:1835-1849(2015)
Cited for: FUNCTION; INTERACTION WITH APH1A/APH1B AND PEN2; SUBCELLULAR LOCATION; CHARACTERIZATION OF VARIANT AD3 ASP-206; Clinical phenotype of G206D mutation in the presenilin 1 gene in pathologically confirmed familial Alzheimer's disease.
Wu Y.Y.; Cheng I.H.; Lee C.C.; Chiu M.J.; Lee M.J.; Chen T.F.; Hsu J.L.;
J. Alzheimers Dis. 25:145-150(2011)
Cited for: VARIANT AD3 ASP-206; Genetic screening in two Iranian families with early-onset Alzheimer's disease identified a novel PSEN1 mutation.
Wang J.C.; Alinaghi S.; Tafakhori A.; Sikora E.; Azcona L.J.; Karkheiran S.; Goate A.; Paisan-Ruiz C.; Darvish H.;
Neurobiol. Aging 62:E15-E17(2018)
Cited for: VARIANTS AD3 PHE-142 AND ASP-206;