UniProtKB/Swiss-Prot Q8IV08: Variant p.Val232Met

5'-3' exonuclease PLD3
Gene: PLD3
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Variant information Variant position:

232 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Type of variant:

US 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 Valine (V) to Methionine (M) at position 232 (V232M, p.Val232Met). 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:

Similar physico-chemical property. Both residues are medium size and hydrophobic. 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:

Found in patients with Alzheimer disease; uncertain significance; does not reduce either amyloid-beta levels or APP expression; no effect on protein maturation or trafficking to lysosomes; partial loss of dimer formation; decreased or complete loss of exonuclease activity toward mitochondrial CpG-rich ssDNA fragments resulting in DNA build-up in the endolysosomal compartment, increased TLR9 pro-inflammatory signaling and increased mitophagy; decreased exonuclease activity toward RNA substrate; decreased (S,S)- BMP synthase activity. Any additional useful information about the variant.
Other resources:

Links to websites of interest for the variant.

Variant rs145999145 [ dbSNP | Ensembl ]

Sequence information Variant position:

232 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Protein sequence length:

490 The length of the canonical sequence.
Location on the sequence:

FYLGSANMDWRSLTQVKELG V VMYNCSCLARDLTKIFEAYW 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                         FYLGSANMDWRSLTQVKELGVVMYNCSCLARDLTKIFEAYW

Mouse                         FYLGSANMDWRSLTQVKELGVVMYNCSCLARDLTKIFEAYW

Rat                           FYLGSANMDWRSLTQVKELGVVMYNCSCLARDLTKIFEAYW

Bovine                        FYLGSANMDWRSLTQVKELGVVMYNCSCLARDLTKIFEAYW

Xenopus laevis                FYIGSANMDWRSLTQVKELGATIYNCSCLAQDLKKIFEAYW

Xenopus tropicalis            FYIGSANMDWRSLTQVKELGATIYNCSCLAEDLKKIFEAYW

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 – 490	5'-3' exonuclease PLD3
Topological domain	60 – 490	Lumenal
Binding site	218 – 218
Glycosylation	236 – 236	N-linked (GlcNAc...) asparagine
Disulfide bond	77 – 239
Disulfide bond	81 – 237
Mutagenesis	228 – 228	K -> R. Decreases exonuclease activity toward CpG-free or CpG-rich ssDNA substrates. Increases mitophagy rate. No effect on protein maturation or trafficking to lysosomes.
Mutagenesis	236 – 236	N -> S. Increases exonuclease activity toward CpG-free ssDNA substrates. Slightly decreases exonuclease activity toward a CpG-rich ATP6 ssDNA sequence. Loss of exonuclease activity toward a CpG-rich ND4L ssDNA sequence. Increases mitophagy rate. No effect on protein maturation or trafficking to lysosomes.
Beta strand	227 – 236

Literature citations
Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer's disease.
Cruchaga C.; Karch C.M.; Jin S.C.; Benitez B.A.; Cai Y.; Guerreiro R.; Harari O.; Norton J.; Budde J.; Bertelsen S.; Jeng A.T.; Cooper B.; Skorupa T.; Carrell D.; Levitch D.; Hsu S.; Choi J.; Ryten M.; Hardy J.; Ryten M.; Trabzuni D.; Weale M.E.; Ramasamy A.; Smith C.; Sassi C.; Bras J.; Gibbs J.R.; Hernandez D.G.; Lupton M.K.; Powell J.; Forabosco P.; Ridge P.G.; Corcoran C.D.; Tschanz J.T.; Norton M.C.; Munger R.G.; Schmutz C.; Leary M.; Demirci F.Y.; Bamne M.N.; Wang X.; Lopez O.L.; Ganguli M.; Medway C.; Turton J.; Lord J.; Braae A.; Barber I.; Brown K.; Passmore P.; Craig D.; Johnston J.; McGuinness B.; Todd S.; Heun R.; Kolsch H.; Kehoe P.G.; Hooper N.M.; Vardy E.R.; Mann D.M.; Pickering-Brown S.; Brown K.; Kalsheker N.; Lowe J.; Morgan K.; David Smith A.; Wilcock G.; Warden D.; Holmes C.; Pastor P.; Lorenzo-Betancor O.; Brkanac Z.; Scott E.; Topol E.; Morgan K.; Rogaeva E.; Singleton A.B.; Hardy J.; Kamboh M.I.; St George-Hyslop P.; Cairns N.; Morris J.C.; Kauwe J.S.; Goate A.M.;
Nature 505:550-554(2014)
Cited for: FUNCTION; POSSIBLE INVOLVEMENT IN ALZHEIMER DISEASE; VARIANT MET-232; TISSUE SPECIFICITY; INTERACTION WITH APP; Rare variants in PLD3 do not affect risk for early-onset Alzheimer disease in a European consortium cohort.
Cacace R.; Van den Bossche T.; Engelborghs S.; Geerts N.; Laureys A.; Dillen L.; Graff C.; Thonberg H.; Chiang H.H.; Pastor P.; Ortega-Cubero S.; Pastor M.A.; Diehl-Schmid J.; Alexopoulos P.; Benussi L.; Ghidoni R.; Binetti G.; Nacmias B.; Sorbi S.; Sanchez-Valle R.; Llado A.; Gelpi E.; Almeida M.R.; Santana I.; Tsolaki M.; Koutroumani M.; Clarimon J.; Lleo A.; Fortea J.; de Mendonca A.; Martins M.; Borroni B.; Padovani A.; Matej R.; Rohan Z.; Vandenbulcke M.; Vandenberghe R.; De Deyn P.P.; Cras P.; van der Zee J.; Sleegers K.; Van Broeckhoven C.;
Hum. Mutat. 36:1226-1235(2015)
Cited for: LACK OF INVOLVEMENT IN ALZHEIMER DISEASE; VARIANTS SER-63; ALA-76; MET-159; CYS-162; SER-173; GLY-175; CYS-188; HIS-222; MET-232; GLN-242; GLY-249; CYS-272; SER-284; VAL-293; LEU-297; TYR-300; PRO-308; ILE-358; ALA-426 AND ARG-429; PLD3 and sporadic Alzheimer's disease risk.
Lambert J.C.; Grenier-Boley B.; Bellenguez C.; Pasquier F.; Campion D.; Dartigues J.F.; Berr C.; Tzourio C.; Amouyel P.;
Nature 520:E1-E1(2015)
Cited for: LACK OF INVOLVEMENT IN ALZHEIMER DISEASE; VARIANT MET-232; PLD3 variants in population studies.
van der Lee S.J.; Holstege H.; Wong T.H.; Jakobsdottir J.; Bis J.C.; Chouraki V.; van Rooij J.G.; Grove M.L.; Smith A.V.; Amin N.; Choi S.H.; Beiser A.S.; Garcia M.E.; van Ijcken W.F.; Pijnenburg Y.A.; Louwersheimer E.; Brouwer R.W.; van den Hout M.C.; Oole E.; Eirkisdottir G.; Levy D.; Rotter J.I.; Emilsson V.; O'Donnell C.J.; Aspelund T.; Uitterlinden A.G.; Launer L.J.; Hofman A.; Boerwinkle E.; Psaty B.M.; DeStefano A.L.; Scheltens P.; Seshadri S.; van Swieten J.C.; Gudnason V.; van der Flier W.M.; Ikram M.A.; van Duijn C.M.;
Nature 520:E2-E3(2015)
Cited for: LACK OF INVOLVEMENT IN ALZHEIMER DISEASE; VARIANT MET-232; PLD3 in non-familial Alzheimer's disease.
Heilmann S.; Drichel D.; Clarimon J.; Fernandez V.; Lacour A.; Wagner H.; Thelen M.; Hernandez I.; Fortea J.; Alegret M.; Blesa R.; Mauleon A.; Roca M.R.; Kornhuber J.; Peters O.; Heun R.; Froelich L.; Huell M.; Heneka M.T.; Ruether E.; Riedel-Heller S.; Scherer M.; Wiltfang J.; Jessen F.; Becker T.; Tarraga L.; Boada M.; Maier W.; Lleo A.; Ruiz A.; Noethen M.M.; Ramirez A.;
Nature 520:E3-E5(2015)
Cited for: LACK OF INVOLVEMENT IN ALZHEIMER DISEASE; VARIANT MET-232; PLD3 gene variants and Alzheimer's disease.
Hooli B.V.; Lill C.M.; Mullin K.; Qiao D.; Lange C.; Bertram L.; Tanzi R.E.;
Nature 520:E7-E8(2015)
Cited for: LACK OF INVOLVEMENT IN ALZHEIMER DISEASE; VARIANT MET-232; Cruchaga & Goate reply.
Cruchaga C.; Goate A.M.;
Nature 520:E10-E10(2015)
Cited for: POSSIBLE INVOLVEMENT IN ALZHEIMER DISEASE; VARIANT MET-232; PLD3 gene and processing of APP.
Fazzari P.; Horre K.; Arranz A.M.; Frigerio C.S.; Saito T.; Saido T.C.; De Strooper B.;
Nature 541:E1-E2(2017)
Cited for: LACK OF INVOLVEMENT IN ALZHEIMER DISEASE; TISSUE SPECIFICITY; CHARACTERIZATION OF VARIANTS MET-232; FUNCTION; MUTAGENESIS OF LYS-418; Phospholipase D3 degrades mitochondrial DNA to regulate nucleotide signaling and APP metabolism.
Van Acker Z.P.; Perdok A.; Hellemans R.; North K.; Vorsters I.; Cappel C.; Dehairs J.; Swinnen J.V.; Sannerud R.; Bretou M.; Damme M.; Annaert W.;
Nat. Commun. 14:2847-2847(2023)
Cited for: FUNCTION; CATALYTIC ACTIVITY; CHARACTERIZATION OF VARIANTS MET-232; SER-284 AND ALA-426; MUTAGENESIS OF MET-6; LYS-228 AND ASN-236; PLD3 and PLD4 synthesize S,S-BMP, a key phospholipid enabling lipid degradation in lysosomes.
Singh S.; Dransfeld U.E.; Ambaw Y.A.; Lopez-Scarim J.; Farese R.V. Jr.; Walther T.C.;
Cell 0:0-0(2024)
Cited for: FUNCTION; CATALYTIC ACTIVITY; SUBCELLULAR LOCATION; MUTAGENESIS OF HIS-201; LYS-203; ASP-208; HIS-416; LYS-418 AND GLU-423; CHARACTERIZATION OF VARIANT MET-232; CHARACTERIZATION OF VARIANT SCA46 PRO-308; Structural and mechanistic insights into disease-associated endolysosomal exonucleases PLD3 and PLD4.
Yuan M.; Peng L.; Huang D.; Gavin A.; Luan F.; Tran J.; Feng Z.; Zhu X.; Matteson J.; Wilson I.A.; Nemazee D.;
Structure 32:766-779.e7(2024)
Cited for: FUNCTION; CATALYTIC ACTIVITY; ACTIVITY REGULATION; BIOPHYSICOCHEMICAL PROPERTIES; CHARACTERIZATION OF VARIANT SCA46 PRO-308; VARIANT MET-232; MUTAGENESIS OF ILE-163; ARG-356 AND PRO-410; Lysosomal endonuclease RNase T2 and PLD exonucleases cooperatively generate RNA ligands for TLR7 activation.
Berouti M.; Lammens K.; Heiss M.; Hansbauer L.; Bauernfried S.; Stoeckl J.; Pinci F.; Piseddu I.; Greulich W.; Wang M.; Jung C.; Froehlich T.; Carell T.; Hopfner K.P.; Hornung V.;
Immunity 57:1482-1496.e8(2024)
Cited for: STRUCTURE BY ELECTRON MICROSCOPY (2.80 ANGSTROMS) OF 60-490; FUNCTION; CATALYTIC ACTIVITY; TISSUE SPECIFICITY; SUBUNIT; DOMAIN; MUTAGENESIS OF HIS-201; HIS-337; HIS-339; ARG-340; HIS-388; HIS-390; TYR-411 AND HIS-416; CHARACTERIZATION OF VARIANT SCA46 PRO-308; CHARACTERIZATION OF VARIANT MET-232;

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