UniProtKB/Swiss-Prot P40692: Variant p.Arg474Trp

DNA mismatch repair protein Mlh1
Gene: MLH1
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Variant information Variant position:

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

LB/B 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 474 (R474W, p.Arg474Trp). 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:

Risk factor for LYNCH2; no effect on MLH1 splicing. Any additional useful information about the variant.
Other resources:

Links to websites of interest for the variant.

Variant rs147939838 [ dbSNP | Ensembl ]

Sequence information Variant position:

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

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

GTSEMSEKRGPTSSNPRKRH R EDSDVEMVEDDSRKEMTAAC 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                         GTSEMSEKRGPTSS--NPRKRHREDSDVEMVEDDSRK-EMTAAC

Mouse                         ETSDAAQKAAPTSSPGSSRKRHREDSDVEMVENASGK-EMT

Rat                           GASEVVAPQRHPSSPGSSRKRHPEDSDVEMMENDSRK-EMT

Slime mold                    KSKEQRQQQSTTTTTTTTTTTATTKSNSPASKNDIKKLQEH

Baker's yeast                 DQPKKKQKLGDYKVPSIADD---EKNALPISKDGYIR----

Fission yeast                 YDNEIIEKVDSANSNKNATNDIKDLQTEEIVEEGNS-----

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 – 756	DNA mismatch repair protein Mlh1
Region	400 – 491	Disordered
Region	410 – 650	Interaction with EXO1
Motif	471 – 474	Nuclear localization signal
Modified residue	477 – 477	Phosphoserine
Mutagenesis	471 – 471	K -> N. Affects binding to importins alpha, including KPNA2, hence may affect import to the nucleus.
Mutagenesis	472 – 472	R -> N. Affects binding to importins alpha, including KPNA2, hence may affect import to the nucleus.

Literature citations
A large fraction of unclassified variants of the mismatch repair genes MLH1 and MSH2 is associated with splicing defects.
Tournier I.; Vezain M.; Martins A.; Charbonnier F.; Baert-Desurmont S.; Olschwang S.; Wang Q.; Buisine M.P.; Soret J.; Tazi J.; Frebourg T.; Tosi M.;
Hum. Mutat. 29:1412-1424(2008)
Cited for: VARIANT LYNCH2 ILE-330 DEL; VARIANTS HIS-41; ARG-67; ARG-77; SER-98; SER-101; ASP-101; LYS-116; MET-117; ASN-126; MET-213; SER-215; SER-216; PHE-260; CYS-265; HIS-265; ASP-320; ALA-326; ILE-330 DEL; TRP-474; GLN-474; ASP-539; PRO-549; THR-551; ARG-585; ARG-603; HIS-607; PRO-619; SER-640; LEU-640; VAL-655; SER-656; ARG-666; THR-681 AND ARG-689;

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.