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UniProtKB/Swiss-Prot P35670: Variant p.Pro992Leu

Copper-transporting ATPase 2
Gene: ATP7B
Chromosomal location: 13q14.3
Variant information

Variant position:  992
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 Proline (P) to Leucine (L) at position 992 (P992L, p.Pro992Leu).
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:  -3
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:  Wilson disease (WD) [MIM:277900]: An autosomal recessive disorder of copper metabolism in which copper cannot be incorporated into ceruloplasmin in liver, and cannot be excreted from the liver into the bile. Copper accumulates in the liver and subsequently in the brain and kidney. The disease is characterized by neurologic manifestations and signs of cirrhosis. {ECO:0000269|PubMed:10051024, ECO:0000269|PubMed:10194254, ECO:0000269|PubMed:10447265, ECO:0000269|PubMed:10453196, ECO:0000269|PubMed:10502776, ECO:0000269|PubMed:10502777, ECO:0000269|PubMed:10544227, ECO:0000269|PubMed:10721669, ECO:0000269|PubMed:10790207, ECO:0000269|PubMed:10942420, ECO:0000269|PubMed:11043508, ECO:0000269|PubMed:11093740, ECO:0000269|PubMed:11180609, ECO:0000269|PubMed:11216666, ECO:0000269|PubMed:11231950, ECO:0000269|PubMed:11243728, ECO:0000269|PubMed:11405812, ECO:0000269|PubMed:11690702, ECO:0000269|PubMed:11954751, ECO:0000269|PubMed:12325021, ECO:0000269|PubMed:12376745, ECO:0000269|PubMed:12544487, ECO:0000269|PubMed:14639035, ECO:0000269|PubMed:14966923, ECO:0000269|PubMed:14986826, ECO:0000269|PubMed:15024742, ECO:0000269|PubMed:15557537, ECO:0000269|PubMed:15811015, ECO:0000269|PubMed:15845031, ECO:0000269|PubMed:15952988, ECO:0000269|PubMed:15967699, ECO:0000269|PubMed:16088907, ECO:0000269|PubMed:16207219, ECO:0000269|PubMed:16283883, ECO:0000269|PubMed:16649058, ECO:0000269|PubMed:17718866, ECO:0000269|PubMed:17823867, ECO:0000269|PubMed:17919502, ECO:0000269|PubMed:17949296, ECO:0000269|PubMed:18203200, ECO:0000269|PubMed:18373411, ECO:0000269|PubMed:19033537, ECO:0000269|PubMed:20333758, ECO:0000269|PubMed:21398519, ECO:0000269|PubMed:21454443, ECO:0000269|PubMed:21645214, ECO:0000269|PubMed:21682854, ECO:0000269|PubMed:22075048, ECO:0000269|PubMed:22240481, ECO:0000269|PubMed:22484412, ECO:0000269|PubMed:22763723, ECO:0000269|PubMed:23159873, ECO:0000269|PubMed:23235335, ECO:0000269|PubMed:23275100, ECO:0000269|PubMed:23333878, ECO:0000269|PubMed:23518715, ECO:0000269|PubMed:23962630, ECO:0000269|PubMed:24476933, ECO:0000269|PubMed:24555712, ECO:0000269|PubMed:24706876, ECO:0000269|PubMed:25704634, ECO:0000269|PubMed:25982861, ECO:0000269|PubMed:26004889, ECO:0000269|PubMed:28856630, ECO:0000269|PubMed:7626145, ECO:0000269|PubMed:8298641, ECO:0000269|PubMed:8533760, ECO:0000269|PubMed:8782057, ECO:0000269|PubMed:8931691, ECO:0000269|PubMed:8938442, ECO:0000269|PubMed:8980283, ECO:0000269|PubMed:9222767, ECO:0000269|PubMed:9311736, ECO:0000269|PubMed:9452121, ECO:0000269|PubMed:9482578, ECO:0000269|PubMed:9554743, ECO:0000269|PubMed:9671269, ECO:0000269|PubMed:9772425, ECO:0000269|PubMed:9829905, ECO:0000269|PubMed:9837819, ECO:0000269|PubMed:9887381}. 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 WD; common mutation; decreased copper transport activity; no effect on ATPase activity.
Any additional useful information about the variant.

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



Sequence information

Variant position:  992
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  1465
The length of the canonical sequence.

Location on the sequence:   FQTSITVLCIACPCSLGLAT  P TAVMVGTGVAAQNGILIKGG
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                         FQTSITVLCIACPCSLGLATPTAVMVGTGVAAQNGILIKGG

Mouse                         FQTSITVLCIACPCSLGLATPTAVMVGTGVAAQNGVLIKGG

Rat                           FQTSITVLCIACPCSLGLATPTAVMVGTGVAAQNGVLIKGG

Sheep                         FQTSITVLCIACPCSLGLATPTAVMVGTGVAAQNGILIKGG

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 – 1465 Copper-transporting ATPase 2
Transmembrane 973 – 994 Helical
Alternative sequence 234 – 1465 RPLSSANQNFNNSETLGHQGSHVVTLQLRIDGMHCKSCVLNIEENIGQLLGVQSIQVSLENKTAQVKYDPSCTSPVALQRAIEALPPGNFKVSLPDGAEGSGTDHRSSSSHSPGSPPRNQVQGTCSTTLIAIAGMTCASCVHSIEGMISQLEGVQQISVSLAEGTATVLYNPSVISPEELRAAIEDMGFEASVVSESCSTNPLGNHSAGNSMVQTTDGTPTSVQEVAPHTGRLPANHAPDILAKSPQSTRAVAPQKCFLQIKGMTCASCVSNIERNLQKEAGVLSVLVALMAGKAEIKYDPEVIQPLEIAQFIQDLGFEAAVMEDYAGSDGNIELTITGMTCASCVHNIESKLTRTNGITYASVALATSKALVKFDPEIIGPRDIIKIIEEIGFHASLAQRNPNAHHLDHKMEIKQWKKSFLCSLVFGIPVMALMIYMLIPSNEPHQSMVLDHNIIPGLSILNLIFFILCTFVQLLGGWYFYVQAYKSLRHRSANMDVLIVLATSIAYVYSLVILVVAVAEKAERSPVTFFDTPPMLFVFIALGRWLEHLAKSKTSEALAKLMSLQATEATVVTLGEDNLIIREEQVPMELVQRGDIVKVVPGGKFPVDGKVLEGNTMADESLITGEAMPVTKKPGSTVIAGSINAHGSVLIKATHVGNDTTLAQIVKLVEEAQMSKAPIQQLADRFSGYFVPFIIIMSTLTLVVWIVIGFIDFGVVQRYFPNPNKHISQTEVIIRFAFQTSITVLCIACPCSLGLATPTAVMVGTGVAAQNGILIKGGKPLEMAHKIKTVMFDKTGTITHGVPRVMRVLLLGDVATLPLRKVLAVVGTAEASSEHPLGVAVTKYCKEELGTETLGYCTDFQAVPGCGIGCKVSNVEGILAHSERPLSAPASHLNEAGSLPAEKDAVPQTFSVLIGNREWLRRNGLTISSDVSDAMTDHEMKGQTAILVAIDGVLCGMIAIADAVKQEAALAVHTLQSMGVDVVLITGDNRKTARAIATQVGINKVFAEVLPSHKVAKVQELQNKGKKVAMVGDGVNDSPALAQADMGVAIGTGTDVAIEAADVVLIRNDLLDVVASIHLSKRTVRRIRINLVLALIYNLVGIPIAAGVFMPIGIVLQPWMGSAAMAASSVSVVLSSLQLKCYKKPDLERYEAQAHGHMKPLTASQVSVHIGMDDRWRDSPRATPWDQVSYVSQVSLSSLTSDKPSRHSAAADDDGDKWSLLLNGRDEEQYI -> ETFIFC. In isoform 5.


Literature citations

Functional characterization of missense mutations in ATP7B: Wilson disease mutation or normal variant?
Forbes J.R.; Cox D.W.;
Am. J. Hum. Genet. 63:1663-1674(1998)
Cited for: CHARACTERIZATION OF VARIANTS WD ASN-765; VAL-769; VAL-776; LEU-778; GLN-778; SER-943; MET-977 AND LEU-992; CHARACTERIZATION OF VARIANT ALA-995;

Mutation analysis of 218 Chinese patients with Wilson disease revealed no correlation between the canine copper toxicosis gene MURR1 and Wilson disease.
Wu Z.Y.; Zhao G.X.; Chen W.J.; Wang N.; Wan B.; Lin M.T.; Murong S.X.; Yu L.;
J. Mol. Med. 84:438-442(2006)
Cited for: VARIANTS WD LEU-778; MET-935; LEU-992; ARG-1268 AND SER-1270;

Distinct clinical courses according to presenting phenotypes and their correlations to ATP7B mutations in a large Wilson's disease cohort.
Lee B.H.; Kim J.H.; Lee S.Y.; Jin H.Y.; Kim K.J.; Lee J.J.; Park J.Y.; Kim G.H.; Choi J.H.; Kim K.M.; Yoo H.W.;
Liver Int. 31:831-839(2011)
Cited for: VARIANTS WD ARG-108; VAL-729; GLN-778; LEU-778; TRP-827; VAL-874; ASP-891; 899-ILE--GLN-907 DEL; GLY-919; ASP-943; SER-943; GLN-969; MET-977; LEU-992; THR-1010; ALA-1024; ILE-1029; ALA-1031; VAL-1035; PHE-1083; TYR-1091; ILE-1106; THR-1148; CYS-1151; SER-1168; SER-1186; MET-1216; ALA-1267; SER-1270; LEU-1273 AND ASP-1295; CHARACTERIZATION OF VARIANTS WD TRP-827; THR-1010; CYS-1151 AND ASP-1295;

Diverse functional properties of Wilson disease ATP7B variants.
Huster D.; Kuehne A.; Bhattacharjee A.; Raines L.; Jantsch V.; Noe J.; Schirrmeister W.; Sommerer I.; Sabri O.; Berr F.; Moessner J.; Stieger B.; Caca K.; Lutsenko S.;
Gastroenterology 142:947-956(2012)
Cited for: CHARACTERIZATION OF VARIANTS WD VAL-85; SER-492; TRP-616; ALA-626; ARG-645; SER-710; LEU-760; ASN-765; VAL-769; LEU-840; THR-857; VAL-874; GLN-969; LEU-992; LEU-1052; LYS-1064; GLN-1069; PHE-1083; VAL-1213; VAL-1222; ARG-1266; SER-1270 AND LEU-1273; CHARACTERIZATION OF VARIANTS ALA-406; LEU-456 AND ARG-832; MUTAGENESIS OF ASP-1027 AND THR-1031; FUNCTION; CATALYTIC ACTIVITY; SUBCELLULAR LOCATION;

Mutational analysis of ATP7B in north Chinese patients with Wilson disease.
Li K.; Zhang W.M.; Lin S.; Wen L.; Wang Z.F.; Xie D.; Wei M.; Qiu Z.Q.; Dai Y.; Lin M.C.; Kung H.F.; Yao F.X.;
J. Hum. Genet. 58:67-72(2013)
Cited for: VARIANTS WD ASN-44; PHE-157; GLY-606; HIS-732; PRO-732; GLY-756; GLN-778; LEU-778; PHE-795; PRO-874; VAL-874; MET-890; GLY-919; ARG-921; ASP-943; TYR-975; TYR-980; PRO-987; LEU-992; CYS-1151; ALA-1178; GLU-1266; SER-1270 AND LEU-1273; VARIANT VAL-929;

Further delineation of the molecular pathology of Wilson disease in the Mediterranean population.
Loudianos G.; Dessi V.; Lovicu M.; Angius A.; Nurchi A.; Sturniolo G.C.; Marcellini M.; Zancan L.; Bragetti P.; Akar N.; Yagci R.; Vegnente A.; Cao A.; Pirastu M.;
Hum. Mutat. 12:89-94(1998)
Cited for: VARIANTS WD VAL-85; SER-492; 608-PHE-ASP-609 DELINS TYR; HIS-642; ARG-645; ILE-665; ARG-691; PHE-747; TRP-778; LEU-840; ASN-918; TRP-919; ASN-921; PRO-933; LEU-992; THR-1003; VAL-1018; TRP-1041; VAL-1089; MET-1146; GLY-1183; THR-1183; MET-1216; ASP-1341 AND SER-1358;

High prevalence of the H1069Q mutation in East German patients with Wilson disease: rapid detection of mutations by limited sequencing and phenotype-genotype analysis.
Caca K.; Ferenci P.; Kuehn H.-J.; Polli C.; Willgerodt H.; Kunath B.; Hermann W.; Moessner J.; Berr F.;
J. Hepatol. 35:575-581(2001)
Cited for: VARIANTS WD TRP-616; ALA-710; SER-710; LEU-760; ASN-765; VAL-769; GLN-969; LEU-992; GLN-1069 AND SER-1270; VARIANTS ALA-406; LEU-456 AND ARG-832;

Mutation spectrum and polymorphisms in ATP7B identified on direct sequencing of all exons in Chinese Han and Hui ethnic patients with Wilson's disease.
Gu Y.-H.; Kodama H.; Du S.-L.; Gu Q.-J.; Sun H.-J.; Ushijima H.;
Clin. Genet. 64:479-484(2003)
Cited for: VARIANTS WD VAL-85; GLY-765; LEU-778; MET-890; GLY-919; MET-935; TYR-975; LEU-992; ARG-1098; THR-1148; LYS-1173 AND ASN-1248; VARIANTS ASP-14; ALA-406; LEU-456; ARG-832; ALA-1140; ASN-1143 AND SER-1245;

Frameshift and nonsense mutations in the gene for ATPase7B are associated with severe impairment of copper metabolism and with an early clinical manifestation of Wilson's disease.
Gromadzka G.; Schmidt H.H.-J.; Genschel J.; Bochow B.; Rodo M.; Tarnacka B.; Litwin T.; Chabik G.; Czlonkowska A.;
Clin. Genet. 68:524-532(2005)
Cited for: VARIANTS WD GLN-616; TYR-639; TYR-653; PRO-776; GLY-778; MET-977; ARG-988; LEU-992; GLN-1069; PRO-1095; MET-1220; LEU-1273 AND ASP-1341;

Genetic and clinical analysis in a cohort of patients with Wilson's disease in southwestern China.
Liu Y.; Zhou H.; Guo H.; Bai Y.;
Arch. Med. Res. 46:164-169(2015)
Cited for: VARIANTS WD LEU-778; GLY-919; LEU-992; LYS-1136 AND GLU-1149; VARIANT LEU-456;

Identification of two novel mutations in the ATP7B gene that cause Wilson's disease.
Zhu H.W.; Tao Z.B.; Su G.; Jin Q.Y.; Zhao L.T.; Zhu J.R.; Yan J.; Yu T.Y.; Ding J.X.; Li Y.M.;
World J. Pediatr. 13:387-391(2017)
Cited for: VARIANTS WD VAL-874; LEU-992; GLU-1010 AND 1331-TYR--ILE-1465 DEL;

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.