UniProtKB/Swiss-Prot Q5S007: Variant p.Gly2019Ser

Leucine-rich repeat serine/threonine-protein kinase 2
Gene: LRRK2
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Variant information Variant position:

2019 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Type of variant:

LP/P [Disclaimer] 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 Serine (S) at position 2019 (G2019S, p.Gly2019Ser). 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
Variant description:

In PARK8; shows an increase in activity in both autophosphorylation and phosphorylation of a generic substrate; results in increased PRDX3 phosphorylation promoting dysregulation of mitochondrial function and oxidative damage; results in increased APP phosphorylation on 'T-743' promoting neurotoxicity in dopaminergic neurons; shows increased kinase activity in the phosphorylation of RAB10; does not inhibit interaction with RAB29; shows a progressive reduction in neurite length and branching; shows distinctive spheroid-like inclusions within both neuronal processes and at intracellular membranous structures; shows lysosomal swelling and reduced retrograde transport of selective cargo between lysosomes and the Golgi apparatus; shows apoptotic mechanism of cell death; no loss of interaction with SEC16A. Any additional useful information about the variant.
Other resources:

Links to websites of interest for the variant.

Variant rs34637584 [ dbSNP | Ensembl ]

Sequence information Variant position:

2019 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Protein sequence length:

2527 The length of the canonical sequence.
Location on the sequence:

NVLLFTLYPNAAIIAKIADY G IAQYCCRMGIKTSEGTPGFR 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                         NVLLFTLYPNAAIIAKIADYGIAQYCCRMGIKTSEGTPGFR

Mouse                         NVLLFTLYPNAAIIAKIADYGIAQYCCRMGIKTSEGTPGFR

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 – 2527	Leucine-rich repeat serine/threonine-protein kinase 2
Domain	1879 – 2138	Protein kinase
Mutagenesis	2017 – 2017	D -> A. Loss of kinase activity. Decreases proteasomal degradation of MAPT; when associated with A-1906 and N-1994. Loss of phosphorylation of RAB10; when associated with G-1441, C-1699, or S-2019.
Mutagenesis	2019 – 2019	G -> S. Decreased membrane association when associated with D-727, D-728, or D-729. Inhibits autophosphorylation and RAB10 phosphorylation when associated with N-1348 or A-2017.
Helix	2018 – 2025

Literature citations
Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity.
West A.B.; Moore D.J.; Biskup S.; Bugayenko A.; Smith W.W.; Ross C.A.; Dawson V.L.; Dawson T.M.;
Proc. Natl. Acad. Sci. U.S.A. 102:16842-16847(2005)
Cited for: SUBCELLULAR LOCATION; CHARACTERIZATION OF VARIANTS PARK8 CYS-1441 AND SER-2019; The familial Parkinsonism gene LRRK2 regulates neurite process morphology.
MacLeod D.; Dowman J.; Hammond R.; Leete T.; Inoue K.; Abeliovich A.;
Neuron 52:587-593(2006)
Cited for: FUNCTION; CHARACTERIZATION OF VARIANTS PARK8 GLY-1441; CYS-1699; SER-2019 AND THR-2020; VARIANT MET-1906; Mutations in LRRK2 increase phosphorylation of peroxiredoxin 3 exacerbating oxidative stress-induced neuronal death.
Angeles D.C.; Gan B.H.; Onstead L.; Zhao Y.; Lim K.L.; Dachsel J.; Melrose H.; Farrer M.; Wszolek Z.K.; Dickson D.W.; Tan E.K.;
Hum. Mutat. 32:1390-1397(2011)
Cited for: FUNCTION; SUBCELLULAR LOCATION; INTERACTION WITH PRDX3; CHARACTERIZATION OF VARIANT PARK8 SER-2019; RAB7L1 interacts with LRRK2 to modify intraneuronal protein sorting and Parkinson's disease risk.
MacLeod D.A.; Rhinn H.; Kuwahara T.; Zolin A.; Di Paolo G.; McCabe B.D.; MacCabe B.D.; Marder K.S.; Honig L.S.; Clark L.N.; Small S.A.; Abeliovich A.;
Neuron 77:425-439(2013)
Cited for: FUNCTION IN RETROGRADE TRANSPORT; INTERACTION WITH RAB29 AND VPS35; SUBCELLULAR LOCATION; CHARACTERIZATION OF VARIANT PARK8 SER-2019; CHARACTERIZATION OF VARIANT MET-1906; Phosphoproteomics reveals that Parkinson's disease kinase LRRK2 regulates a subset of Rab GTPases.
Steger M.; Tonelli F.; Ito G.; Davies P.; Trost M.; Vetter M.; Wachter S.; Lorentzen E.; Duddy G.; Wilson S.; Baptista M.A.; Fiske B.K.; Fell M.J.; Morrow J.A.; Reith A.D.; Alessi D.R.; Mann M.;
Elife 5:0-0(2016)
Cited for: FUNCTION; CATALYTIC ACTIVITY; COFACTOR; ACTIVITY REGULATION; INTERACTION WITH RAB8A; RAB10 AND RAB12; CHARACTERIZATION OF VARIANTS PARK8 HIS-1441; CYS-1441; GLY-1441; CYS-1699; HIS-1728; SER-2019; THR-2020; SER-2031 AND ARG-2385; MUTAGENESIS OF ASP-1994; LRRK2 Promotes Tau Accumulation, Aggregation and Release.
Guerreiro P.S.; Gerhardt E.; Lopes da Fonseca T.; Baehr M.; Outeiro T.F.; Eckermann K.;
Mol. Neurobiol. 53:3124-3135(2016)
Cited for: FUNCTION; INTERACTION WITH MAPT; SUBCELLULAR LOCATION; CHARACTERIZATION OF VARIANT PAR8 SER-2019; MUTAGENESIS OF LYS-1906; ASP-1994 AND ASP-2017; Systematic proteomic analysis of LRRK2-mediated Rab GTPase phosphorylation establishes a connection to ciliogenesis.
Steger M.; Diez F.; Dhekne H.S.; Lis P.; Nirujogi R.S.; Karayel O.; Tonelli F.; Martinez T.N.; Lorentzen E.; Pfeffer S.R.; Alessi D.R.; Mann M.;
Elife 6:0-0(2017)
Cited for: FUNCTION; CATALYTIC ACTIVITY; COFACTOR; CHARACTERIZATION OF VARIANTS PARK8 GLY-1441; CYS-1699 AND SER-2019; MUTAGENESIS OF ASP-2017; Phosphorylation of amyloid precursor protein by mutant LRRK2 promotes AICD activity and neurotoxicity in Parkinson's disease.
Chen Z.C.; Zhang W.; Chua L.L.; Chai C.; Li R.; Lin L.; Cao Z.; Angeles D.C.; Stanton L.W.; Peng J.H.; Zhou Z.D.; Lim K.L.; Zeng L.; Tan E.K.;
Sci. Signal. 10:0-0(2017)
Cited for: FUNCTION; CATALYTIC ACTIVITY; COFACTOR; INTERACTION WITH APP; PHOSPHORYLATION AT SER-910 AND SER-935; CHARACTERIZATION OF VARIANTS PARK8 GLY-1441 AND SER-2019; MUTAGENESIS OF ASP-1994; Interrogating Parkinson's disease LRRK2 kinase pathway activity by assessing Rab10 phosphorylation in human neutrophils.
Fan Y.; Howden A.J.M.; Sarhan A.R.; Lis P.; Ito G.; Martinez T.N.; Brockmann K.; Gasser T.; Alessi D.R.; Sammler E.M.;
Biochem. J. 475:23-44(2018)
Cited for: FUNCTION; CATALYTIC ACTIVITY; ACTIVITY REGULATION; TISSUE SPECIFICITY; CHARACTERIZATION OF VARIANT PARK8 SER-2019; PHOSPHORYLATION AT SER-935; A pathway for Parkinson's Disease LRRK2 kinase to block primary cilia and Sonic hedgehog signaling in the brain.
Dhekne H.S.; Yanatori I.; Gomez R.C.; Tonelli F.; Diez F.; Schuele B.; Steger M.; Alessi D.R.; Pfeffer S.R.;
Elife 7:0-0(2018)
Cited for: FUNCTION; CATALYTIC ACTIVITY; VARIANTS PARK8 GLY-1441 AND SER-2019; Rab29 activation of the Parkinson's disease-associated LRRK2 kinase.
Purlyte E.; Dhekne H.S.; Sarhan A.R.; Gomez R.; Lis P.; Wightman M.; Martinez T.N.; Tonelli F.; Pfeffer S.R.; Alessi D.R.;
EMBO J. 37:1-18(2018)
Cited for: FUNCTION; CATALYTIC ACTIVITY; ACTIVITY REGULATION; SUBCELLULAR LOCATION; PHOSPHORYLATION AT SER-910; SER-935; SER-955; SER-973 AND SER-1292; CHARACTERIZATION OF VARIANTS PARK8 CYS-1441; GLY-1441; HIS-1441; CYS-1699; HIS-1728; SER-2019; THR-2020; SER-2031 AND ARG-2385; MUTAGENESIS OF CYS-727; LEU-728; LEU-729; LEU-760; LEU-761; LEU-762; LEU-789; LEU-790; LEU-791; THR-1348; ARG-1441; TYR-1699; ASP-2017 AND GLY-2019; Crystal structure of the WD40 domain dimer of LRRK2.
Zhang P.; Fan Y.; Ru H.; Wang L.; Magupalli V.G.; Taylor S.S.; Alessi D.R.; Wu H.;
Proc. Natl. Acad. Sci. U.S.A. 116:1579-1584(2019)
Cited for: X-RAY CRYSTALLOGRAPHY (2.70 ANGSTROMS) OF 2142-2527; FUNCTION; CATALYTIC ACTIVITY; SUBUNIT; DOMAIN; PHOSPHORYLATION AT SER-935 AND SER-1292; CHARACTERIZATION OF VARIANTS PARK8 GLY-1441; SER-2019; ASP-2175; TYR-2189; ILE-2356; ARG-2385; MET-2390 AND ILE-2439; MUTAGENESIS OF ASP-2017; LEU-2343; PHE-2344; SER-2345; TYR-2346; HIS-2391; ARG-2394; GLU-2395; MET-2408 AND SER-2409; Identification of a novel LRRK2 mutation linked to autosomal dominant parkinsonism: evidence of a common founder across European populations.
Kachergus J.M.; Mata I.F.; Hulihan M.; Taylor J.P.; Lincoln S.; Aasly J.O.; Gibson J.M.; Ross O.A.; Lynch T.; Wiley J.; Payami H.; Nutt J.; Maraganore D.M.; Czyzewski K.; Styczynska M.; Wszolek Z.K.; Farrer M.J.; Toft M.;
Am. J. Hum. Genet. 76:672-680(2005)
Cited for: VARIANT PARK8 SER-2019; Clinical and positron emission tomography of Parkinson's disease caused by LRRK2.
Hernandez D.G.; Paisan-Ruiz C.; McInerney-Leo A.; Jain S.; Meyer-Lindenberg A.; Evans E.W.; Berman K.F.; Johnson J.; Auburger G.; Schaeffer A.A.; Lopez G.J.; Nussbaum R.L.; Singleton A.B.;
Ann. Neurol. 57:453-456(2005)
Cited for: VARIANT PARK8 SER-2019; Clinical features of LRRK2-associated Parkinson's disease in central Norway.
Aasly J.O.; Toft M.; Fernandez-Mata I.; Kachergus J.M.; Hulihan M.; White L.R.; Farrer M.J.;
Ann. Neurol. 57:762-765(2005)
Cited for: VARIANT PARK8/PD SER-2019; G2019S LRRK2 mutation in French and North African families with Parkinson's disease.
Lesage S.; Ibanez P.; Lohmann E.; Pollak P.; Tison F.; Tazir M.; Leutenegger A.-L.; Guimaraes J.; Bonnet A.-M.; Agid Y.; Duerr A.; Brice A.;
Ann. Neurol. 58:784-787(2005)
Cited for: VARIANT PARK8 SER-2019; Genetic and clinical identification of Parkinson's disease patients with LRRK2 G2019S mutation.
Deng H.; Le W.; Guo Y.; Hunter C.B.; Xie W.; Jankovic J.;
Ann. Neurol. 57:933-934(2005)
Cited for: VARIANT PARK8 SER-2019; Type and frequency of mutations in the LRRK2 gene in familial and sporadic Parkinson's disease.
Berg D.; Schweitzer K.; Leitner P.; Zimprich A.; Lichtner P.; Belcredi P.; Bruessel T.; Schulte C.; Maass S.; Naegele T.;
Brain 128:3000-3011(2005)
Cited for: VARIANTS PARK8 MET-793; ARG-930; CYS-1096; THR-1228; SER-2019 AND THR-2020; VARIANT LYS-551; Mutations in the gene LRRK2 encoding dardarin (PARK8) cause familial Parkinson's disease: clinical, pathological, olfactory and functional imaging and genetic data.
Khan N.L.; Jain S.; Lynch J.M.; Pavese N.; Abou-Sleiman P.M.; Holton J.L.; Healy D.G.; Gilks W.P.; Sweeney M.G.; Ganguly M.; Gibbons V.; Gandhi S.; Vaughan J.; Eunson L.H.; Katzenschlager R.; Gayton J.; Lennox G.; Revesz T.; Nicholl D.; Bhatia K.P.; Quinn N.; Brooks D.; Lees A.J.; Davis M.B.; Piccini P.; Singleton A.B.; Wood N.W.;
Brain 128:2786-2796(2005)
Cited for: VARIANTS PARK8 CYS-1699; HIS-1941; SER-2019 AND ILE-2356; Comprehensive analysis of the LRRK2 gene in sixty families with Parkinson's disease.
Di Fonzo A.; Tassorelli C.; De Mari M.; Chien H.F.; Ferreira J.; Rohe C.F.; Riboldazzi G.; Antonini A.; Albani G.; Mauro A.; Marconi R.; Abbruzzese G.; Lopiano L.; Fincati E.; Guidi M.; Marini P.; Stocchi F.; Onofrj M.; Toni V.; Tinazzi M.; Fabbrini G.; Lamberti P.; Vanacore N.; Meco G.; Leitner P.; Uitti R.J.; Wszolek Z.K.; Gasser T.; Simons E.J.; Breedveld G.J.; Goldwurm S.; Pezzoli G.; Sampaio C.; Barbosa E.; Martignoni E.; Oostra B.A.; Bonifati V.;
Eur. J. Hum. Genet. 14:322-331(2006)
Cited for: VARIANTS PARK8 VAL-1371; CYS-1441 AND SER-2019; The G6055A (G2019S) mutation in LRRK2 is frequent in both early and late onset Parkinson's disease and originates from a common ancestor.
Goldwurm S.; Di Fonzo A.; Simons E.J.; Rohe C.F.; Zini M.; Canesi M.; Tesei S.; Zecchinelli A.; Antonini A.; Mariani C.; Meucci N.; Sacilotto G.; Sironi F.; Salani G.; Ferreira J.; Chien H.F.; Fabrizio E.; Vanacore N.; Dalla Libera A.; Stocchi F.; Diroma C.; Lamberti P.; Sampaio C.; Meco G.; Barbosa E.; Bertoli-Avella A.M.; Breedveld G.J.; Oostra B.A.; Pezzoli G.; Bonifati V.;
J. Med. Genet. 42:E65-E65(2005)
Cited for: VARIANT PARK8 SER-2019; Genetic screening for a single common LRRK2 mutation in familial Parkinson's disease.
Nichols W.C.; Pankratz N.; Hernandez D.; Paisan-Ruiz C.; Jain S.; Halter C.A.; Michaels V.E.; Reed T.; Rudolph A.; Shults C.W.; Singleton A.; Foroud T.;
Lancet 365:410-412(2005)
Cited for: VARIANT PARK8 SER-2019; A frequent LRRK2 gene mutation associated with autosomal dominant Parkinson's disease.
Di Fonzo A.; Rohe C.F.; Ferreira J.; Chien H.F.; Vacca L.; Stocchi F.; Guedes L.; Fabrizio E.; Manfredi M.; Vanacore N.; Goldwurm S.; Breedveld G.J.; Sampaio C.; Meco G.; Barbosa E.; Oostra B.A.; Bonifati V.;
Lancet 365:412-415(2005)
Cited for: VARIANT PARK8 SER-2019; A common LRRK2 mutation in idiopathic Parkinson's disease.
Gilks W.P.; Abou-Sleiman P.M.; Gandhi S.; Jain S.; Singleton A.; Lees A.J.; Shaw K.; Bhatia K.P.; Bonifati V.; Quinn N.P.; Lynch J.M.; Healy D.G.; Holton J.L.; Revesz T.; Wood N.W.;
Lancet 365:415-416(2005)
Cited for: VARIANT PARK8 SER-2019; LRRK2 mutations and Parkinsonism.
Toft M.; Mata I.F.; Kachergus J.M.; Ross O.A.; Farrer M.J.;
Lancet 365:1229-1230(2005)
Cited for: VARIANT PARK8 SER-2019; Escaping Parkinson's disease: a neurologically healthy octogenarian with the LRRK2 G2019S mutation.
Kay D.M.; Kramer P.; Higgins D.S.; Zabetian C.P.; Payami H.;
Mov. Disord. 20:1077-1078(2005)
Cited for: VARIANT SER-2019; Parkinson's disease and LRRK2: frequency of a common mutation in U.S. movement disorder clinics.
Kay D.M.; Zabetian C.P.; Factor S.A.; Nutt J.G.; Samii A.; Griffith A.; Bird T.D.; Kramer P.; Higgins D.S.; Payami H.;
Mov. Disord. 21:519-523(2006)
Cited for: VARIANT PARK8 SER-2019; Lrrk2 pathogenic substitutions in Parkinson's disease.
Mata I.F.; Kachergus J.M.; Taylor J.P.; Lincoln S.; Aasly J.; Lynch T.; Hulihan M.M.; Cobb S.A.; Wu R.-M.; Lu C.-S.; Lahoz C.; Wszolek Z.K.; Farrer M.J.;
Neurogenetics 6:171-177(2005)
Cited for: VARIANTS PARK8 CYS-1441; GLY-1441; HIS-1441; GLN-1514; SER-1542; GLU-1598; PRO-1628; CYS-1699; THR-1869; THR-2012; SER-2019; THR-2020 AND ARG-2385; VARIANTS PRO-119; LYS-551; VAL-723; MET-793; VAL-1122; ALA-1262; HIS-1398; THR-1646; THR-1647; ASP-2081; LEU-2119; ILE-2261 AND THR-2397; LRRK2 gene in Parkinson disease: mutation analysis and case control association study.
Paisan-Ruiz C.; Lang A.E.; Kawarai T.; Sato C.; Salehi-Rad S.; Fisman G.K.; Al-Khairallah T.; St George-Hyslop P.H.; Singleton A.; Rogaeva E.;
Neurology 65:696-700(2005)
Cited for: VARIANTS PARK8 VAL-1371 AND SER-2019; VARIANTS HIS-1398 AND THR-2397; LRRK2 mutations in Parkinson disease.
Farrer M.; Stone J.; Mata I.F.; Lincoln S.; Kachergus J.; Hulihan M.; Strain K.J.; Maraganore D.M.;
Neurology 65:738-740(2005)
Cited for: VARIANTS PARK8 MET-793; THR-1869 AND SER-2019; A clinic-based study of the LRRK2 gene in Parkinson disease yields new mutations.
Zabetian C.P.; Samii A.; Mosley A.D.; Roberts J.W.; Leis B.C.; Yearout D.; Raskind W.H.; Griffith A.;
Neurology 65:741-744(2005)
Cited for: VARIANTS PARK8 CYS-1441; HIS-1441 AND SER-2019; LRRK2 G2019S is a common mutation in Spanish patients with late-onset Parkinson's disease.
Infante J.; Rodriguez E.; Combarros O.; Mateo I.; Fontalba A.; Pascual J.; Oterino A.; Polo J.M.; Leno C.; Berciano J.;
Neurosci. Lett. 395:224-226(2006)
Cited for: VARIANT PARK8 SER-2019; Clinical traits of LRRK2-associated Parkinson's disease in Ireland: a link between familial and idiopathic PD.
Gosal D.; Ross O.A.; Wiley J.; Irvine G.B.; Johnston J.A.; Toft M.; Mata I.F.; Kachergus J.; Hulihan M.; Taylor J.P.; Lincoln S.J.; Farrer M.J.; Lynch T.; Mark Gibson J.;
Parkinsonism Relat. Disord. 11:349-352(2005)
Cited for: VARIANT PARK8 SER-2019; LRRK2 mutations in Spanish patients with Parkinson disease: frequency, clinical features, and incomplete penetrance.
Gaig C.; Ezquerra M.; Marti M.J.; Munoz E.; Valldeoriola F.; Tolosa E.;
Arch. Neurol. 63:377-382(2006)
Cited for: VARIANTS PARK8 CYS-1441; GLY-1441 AND SER-2019; Comprehensive analysis of LRRK2 in publicly available Parkinson's disease cases and neurologically normal controls.
Paisan-Ruiz C.; Nath P.; Washecka N.; Gibbs J.R.; Singleton A.B.;
Hum. Mutat. 29:485-490(2008)
Cited for: VARIANTS PARK8 VAL-712; LEU-1728; HIS-1728; SER-2019; MET-2141; HIS-2143 AND HIS-2466; VARIANTS SER-228; VAL-716; GLU-871; PHE-1870 AND LYS-2395; Systematic review and UK-based study of PARK2 (parkin), PINK1, PARK7 (DJ-1) and LRRK2 in early-onset Parkinson's disease.
Kilarski L.L.; Pearson J.P.; Newsway V.; Majounie E.; Knipe M.D.; Misbahuddin A.; Chinnery P.F.; Burn D.J.; Clarke C.E.; Marion M.H.; Lewthwaite A.J.; Nicholl D.J.; Wood N.W.; Morrison K.E.; Williams-Gray C.H.; Evans J.R.; Sawcer S.J.; Barker R.A.; Wickremaratchi M.M.; Ben-Shlomo Y.; Williams N.M.; Morris H.R.;
Mov. Disord. 27:1522-1529(2012)
Cited for: VARIANT PARK8 SER-2019; Leucine-rich repeat kinase 2 regulates Sec16A at ER exit sites to allow ER-Golgi export.
Cho H.J.; Yu J.; Xie C.; Rudrabhatla P.; Chen X.; Wu J.; Parisiadou L.; Liu G.; Sun L.; Ma B.; Ding J.; Liu Z.; Cai H.;
EMBO J. 33:2314-2331(2014)
Cited for: CHARACTERIZATION OF VARIANTS PARK8 CYS-1441; CYS-1699 AND SER-2019; CHARACTERIZATION OF VARIANT ARG-2385; FUNCTION; SUBCELLULAR LOCATION; INTERACTION WITH SEC16A; MUTAGENESIS OF LYS-1347 AND ASP-1994;

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.