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UniProtKB/Swiss-Prot Q8N653: Variant p.Gly248Arg

Leucine-zipper-like transcriptional regulator 1
Gene: LZTR1
Variant information

Variant position:  248
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 Glycine (G) to Arginine (R) at position 248 (G248R, p.Gly248Arg).
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 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:  Glioma (GLM) [MIM:137800]: Gliomas are benign or malignant central nervous system neoplasms derived from glial cells. They comprise astrocytomas and glioblastoma multiforme that are derived from astrocytes, oligodendrogliomas derived from oligodendrocytes and ependymomas derived from ependymocytes. {ECO:0000269|PubMed:30442766}. Note=The protein represented in this entry may be involved in disease pathogenesis.
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.

Involvement in disease:  Noonan syndrome 10 (NS10) [MIM:616564]: A form of Noonan syndrome, a disease characterized by short stature, facial dysmorphic features such as hypertelorism, a downward eyeslant and low-set posteriorly rotated ears, and a high incidence of congenital heart defects and hypertrophic cardiomyopathy. Other features can include a short neck with webbing or redundancy of skin, deafness, motor delay, variable intellectual deficits, multiple skeletal defects, cryptorchidism, and bleeding diathesis. Individuals with Noonan syndrome are at risk of juvenile myelomonocytic leukemia, a myeloproliferative disorder characterized by excessive production of myelomonocytic cells. NS10 inheritance is autosomal dominant. {ECO:0000269|PubMed:25795793, ECO:0000269|PubMed:29959388, ECO:0000269|PubMed:30368668, ECO:0000269|PubMed:30442762, ECO:0000269|PubMed:30442766, ECO:0000269|PubMed:30481304}. 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 NS10 and GLM; increased RAS-MAPK signaling; decreased ubiquitination of Ras; decreased stability; no effect on localization to Golgi apparatus.
Any additional useful information about the variant.

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



Sequence information

Variant position:  248
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  840
The length of the canonical sequence.

Location on the sequence:   CCNFPVAVCRDKMFVFSGQS  G AKITNNLFQFEFKDKTWTRI
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                         CCNFPVAVCRDKMFVFSGQSGAKITNNLFQFEFKDKTWTRI

Mouse                         CCNFPVAVCRDKMFVFSGQSGAKITNNLFQFEFKDKTWTRI

Drosophila                    CCNFPVAVARDAMYVFSGQSGLQITNSLFEFHFKTRTWRRI

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 – 840 Leucine-zipper-like transcriptional regulator 1
Repeat 239 – 285 Kelch 4


Literature citations

Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome.
Yamamoto G.L.; Aguena M.; Gos M.; Hung C.; Pilch J.; Fahiminiya S.; Abramowicz A.; Cristian I.; Buscarilli M.; Naslavsky M.S.; Malaquias A.C.; Zatz M.; Bodamer O.; Majewski J.; Jorge A.A.; Pereira A.C.; Kim C.A.; Passos-Bueno M.R.; Bertola D.R.;
J. Med. Genet. 52:413-421(2015)
Cited for: INVOLVEMENT IN NS10; VARIANTS NS10 CYS-119; ASN-247; ARG-248; CYS-284 AND TYR-287; VARIANTS LEU-447 AND VAL-647;

LZTR1 is a regulator of RAS ubiquitination and signaling.
Bigenzahn J.W.; Collu G.M.; Kartnig F.; Pieraks M.; Vladimer G.I.; Heinz L.X.; Sedlyarov V.; Schischlik F.; Fauster A.; Rebsamen M.; Parapatics K.; Blomen V.A.; Mueller A.C.; Winter G.E.; Kralovics R.; Brummelkamp T.R.; Mlodzik M.; Superti-Furga G.;
Science 362:1171-1177(2018)
Cited for: FUNCTION; SUBCELLULAR LOCATION; INTERACTION WITH CUL3; VARIANTS GLM ARG-105; GLY-198; ARG-248; ILE-288 AND TRP-810; CHARACTERIZATION OF VARIANTS GLM ARG-105; GLY-198; ARG-248; ILE-288 AND TRP-810; CHARACTERIZATION OF VARIANTS NS10 CYS-119; ASN-247; ARG-248 AND TYR-287; CHARACTERIZATION OF VARIANTS SWNTS2 LEU-122; ARG-404; GLY-456; GLN-466; LEU-520; CYS-688 AND ILE-813;

Dominant Noonan syndrome-causing LZTR1 mutations specifically affect the kelch domain substrate-recognition surface and enhance RAS-MAPK signaling.
Motta M.; Fidan M.; Bellacchio E.; Pantaleoni F.; Schneider-Heieck K.; Coppola S.; Borck G.; Salviati L.; Zenker M.; Cirstea I.C.; Tartaglia M.;
Hum. Mol. Genet. 0:0-0(2018)
Cited for: FUNCTION; SUBCELLULAR LOCATION; CHARACTERIZATION OF VARIANTS NS2 ASP-121; ALA-217; GLN-563 AND THR-821; CHARACTERIZATION OF VARIANTS NS10 ASN-247; ARG-248 AND CYS-284; CHARACTERIZATION OF VARIANTS SWNTS2 GLN-170; ARG-286 AND ARG-400; MUTAGENESIS OF MET-91 AND TYR-193;

Delineation of LZTR1 mutation-positive patients with Noonan syndrome and identification of LZTR1 binding to RAF1-PPP1CB complexes.
Umeki I.; Niihori T.; Abe T.; Kanno S.I.; Okamoto N.; Mizuno S.; Kurosawa K.; Nagasaki K.; Yoshida M.; Ohashi H.; Inoue S.I.; Matsubara Y.; Fujiwara I.; Kure S.; Aoki Y.;
Hum. Genet. 138:21-35(2019)
Cited for: VARIANTS NS10 SER-143; ARG-248; ASN-253 DEL; GLN-283 AND PRO-554; VARIANT NS2 HIS-701; INTERACTION WITH RAF1; SHOC2 AND PPP1CB;

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.