UniProtKB/Swiss-Prot Q9Y6X9: Variant p.Arg252Trp

• Variant information
• Sequence information
• Literature citations
• All

Variant information

Variant position: 252 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 Arginine (R) to Tryptophan (W) at position 252 (R252W, p.Arg252Trp). 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 large size and basic (R) to large size and aromatic (W) 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
Variant description: In CMT2Z; slightly decreased ATPase activity; increases HUSH-dependent gene silencing. Any additional useful information about the variant.
Other resources: Links to websites of interest for the variant.

• Variant rs864309503 [ dbSNP | Ensembl ]

Sequence information

Variant position: 252 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Protein sequence length: 1032 The length of the canonical sequence.
Location on the sequence: GTKPERRSFRAYAAVLYIDP R MRIFIHGHKVQTKRLSCCLY 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	2 – 1032	ATPase MORC2
Mutagenesis	266 – 266	R -> A. Increases HUSH-dependent gene silencing.

Literature citations

MORC2 mutations cause axonal Charcot-Marie-Tooth disease with pyramidal signs.
Albulym O.M.; Kennerson M.L.; Harms M.B.; Drew A.P.; Siddell A.H.; Auer-Grumbach M.; Pestronk A.; Connolly A.; Baloh R.H.; Zuchner S.; Reddel S.W.; Nicholson G.A.;
Ann. Neurol. 79:419-427(2016)
Cited for: VARIANTS CMT2Z GLU-96; GLY-236; TRP-252 AND ARG-444; VARIANTS CYS-248; HIS-283; HIS-466; CYS-585 AND GLY-757; Mutations in the MORC2 gene cause axonal Charcot-Marie-Tooth disease.
Sevilla T.; Lupo V.; Martinez-Rubio D.; Sancho P.; Sivera R.; Chumillas M.J.; Garcia-Romero M.; Pascual-Pascual S.I.; Muelas N.; Dopazo J.; Vilchez J.J.; Palau F.; Espinos C.;
Brain 139:62-72(2016)
Cited for: VARIANTS CMT2Z LEU-87 AND TRP-252; Clinical and mutational spectrum of Charcot-Marie-Tooth disease type 2Z caused by MORC2 variants in Japan.
Ando M.; Okamoto Y.; Yoshimura A.; Yuan J.H.; Hiramatsu Y.; Higuchi Y.; Hashiguchi A.; Mitsui J.; Ishiura H.; Fukumura S.; Matsushima M.; Ochi N.; Tsugawa J.; Morishita S.; Tsuji S.; Takashima H.;
Eur. J. Neurol. 24:1274-1282(2017)
Cited for: VARIANTS CMT2Z TRP-252; CYS-394; ARG-400; TYR-407 AND VAL-431; VARIANTS SER-209; MET-228 AND LYS-906; Hyperactivation of HUSH complex function by Charcot-Marie-Tooth disease mutation in MORC2.
Tchasovnikarova I.A.; Timms R.T.; Douse C.H.; Roberts R.C.; Dougan G.; Kingston R.E.; Modis Y.; Lehner P.J.;
Nat. Genet. 49:1035-1044(2017)
Cited for: CHARACTERIZATION OF VARIANT CMT2Z TRP-252; FUNCTION; SUBCELLULAR LOCATION; INTERACTION WITH TASOR AND MPHOSPH8; MUTAGENESIS OF ASN-39 AND ASP-68; CATALYTIC ACTIVITY; DSDNA-BINDING; De Novo Variants in the ATPase Module of MORC2 Cause a Neurodevelopmental Disorder with Growth Retardation and Variable Craniofacial Dysmorphism.
Guillen Sacoto M.J.; Tchasovnikarova I.A.; Torti E.; Forster C.; Andrew E.H.; Anselm I.; Baranano K.W.; Briere L.C.; Cohen J.S.; Craigen W.J.; Cytrynbaum C.; Ekhilevitch N.; Elrick M.J.; Fatemi A.; Fraser J.L.; Gallagher R.C.; Guerin A.; Haynes D.; High F.A.; Inglese C.N.; Kiss C.; Koenig M.K.; Krier J.; Lindstrom K.; Marble M.; Meddaugh H.; Moran E.S.; Morel C.F.; Mu W.; Muller E.A. II; Nance J.; Natowicz M.R.; Numis A.L.; Ostrem B.; Pappas J.; Stafstrom C.E.; Streff H.; Sweetser D.A.; Szybowska M.; Walker M.A.; Wang W.; Weiss K.; Weksberg R.; Wheeler P.G.; Yoon G.; Kingston R.E.; Juusola J.;
Am. J. Hum. Genet. 107:352-363(2020)
Cited for: INVOLVEMENT IN DIGFAN; VARIANTS DIGFAN ILE-24; LYS-27; LEU-87; VAL-88; CYS-132; SER-266; ARG-388; CYS-394 AND PHE-413; CHARACTERIZATION OF VARIANTS DIGFAN ILE-24; LYS-27; LEU-87; CYS-132; SER-266; CHARACTERIZATION OF VARIANTS CMT2Z GLY-236; TRP-252; FUNCTION; Neuropathic MORC2 mutations perturb GHKL ATPase dimerization dynamics and epigenetic silencing by multiple structural mechanisms.
Douse C.H.; Bloor S.; Liu Y.; Shamin M.; Tchasovnikarova I.A.; Timms R.T.; Lehner P.J.; Modis Y.;
Nat. Commun. 9:651-651(2018)
Cited for: X-RAY CRYSTALLOGRAPHY (1.81 ANGSTROMS) OF 1-603 OF WILD-TYPE; X-RAY CRYSTALLOGRAPHY (1.81 ANGSTROMS) OF 1-603 OF; X-RAY CRYSTALLOGRAPHY (1.81 ANGSTROMS) OF 1-603 OF VARIANT CMT2Z LEU-87; X-RAY CRYSTALLOGRAPHY (1.81 ANGSTROMS) OF 1-603 OF VARIANT ARG-424 IN COMPLEX WITH ATP; MAGNESIUM AND ZINC; CHARACTERIZATION OF VARIANTS CMT2Z LEU-87 AND TRP-252; CHARACTERIZATION OF VARIANT ARG-424; FUNCTION; CATALYTIC ACTIVITY; SUBUNIT; MUTAGENESIS OF TYR-18; ASN-39; ARG-266; ARG-319; ARG-326; ARG-329; ARG-333; ARG-344; ARG-351 AND ARG-358;