UniProtKB/SwissProt variant VAR

Variant information

Variant position:

574

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 Arginine (R) to Proline (P) at position 574 (R574P, p.Arg574Pro).

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 medium size and hydrophobic (P)

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:

Pitt-Hopkins syndrome (PTHS) [MIM:610954]: A syndrome characterized by mental retardation, wide mouth and distinctive facial features, and intermittent hyperventilation followed by apnea. Features include intellectual disability with severe speech impairment, normal growth parameters at birth, postnatal microcephaly, breathing anomalies, severe motor developmental delay, motor incoordination, ocular anomalies, constipation, seizures, typical behavior and subtle brain abnormalities. {ECO:0000269|PubMed:17436254, ECO:0000269|PubMed:17436255, ECO:0000269|PubMed:18728071, ECO:0000269|PubMed:19235238, ECO:0000269|PubMed:20184619, ECO:0000269|PubMed:22045651, ECO:0000269|PubMed:22777675, ECO:0000269|PubMed:25356899}. 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 PTHS; mislocalized to small spherical punctae that are dispersed throughout the nucleus; can attenuate homo- and heterodimer formation; affects transcriptional activity in a context-dependent manner.

Any additional useful information about the variant.

Other resources:

Links to websites of interest for the variant.

Variant rs121909123 [ dbSNP | Ensembl ]

Sequence information

Variant position:

574

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

Protein sequence length:

667

The length of the canonical sequence.

Location on the sequence:

TPEQKAEREKERRMANNARE R LRVRDINEAFKELGRMVQLH

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                         TPEQKAEREKERRMANNARERLRVRDINEAFKELGRMVQLH

                              TPEQKAEREKERRMANNARERLRVRDINEAFKELGRMVQLH

Mouse                         TPEQKAEREKERRMANNARERLRVRDINEAFKELGRMVQLH

Rat                           TPEQKAEREKERRMANNARERLRVRDINEAFKELGRMVQLH

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 – 667	Transcription factor 4
Domain	564 – 617	bHLH
Helix	565 – 594

Literature citations

Functional analysis of TCF4 missense mutations that cause Pitt-Hopkins syndrome.
Forrest M.; Chapman R.M.; Doyle A.M.; Tinsley C.L.; Waite A.; Blake D.J.;
Hum. Mutat. 33:1676-1686(2012)
Cited for: SUBCELLULAR LOCATION; CHARACTERIZATION OF VARIANTS PTHS VAL-358; GLY-535; PRO-574; TRP-576 AND VAL-610;

Further delineation of Pitt-Hopkins syndrome: phenotypic and genotypic description of 16 novel patients.
Zweier C.; Sticht H.; Bijlsma E.K.; Clayton-Smith J.; Boonen S.E.; Fryer A.; Greally M.T.; Hoffmann L.; den Hollander N.S.; Jongmans M.; Kant S.G.; King M.D.; Lynch S.A.; McKee S.; Midro A.T.; Park S.M.; Ricotti V.; Tarantino E.; Wessels M.; Peippo M.; Rauch A.;
J. Med. Genet. 45:738-744(2008)
Cited for: VARIANTS PTHS VAL-358; PRO-574 AND HIS-578;

Novel comprehensive diagnostic strategy in Pitt-Hopkins syndrome: clinical score and further delineation of the TCF4 mutational spectrum.
Whalen S.; Heron D.; Gaillon T.; Moldovan O.; Rossi M.; Devillard F.; Giuliano F.; Soares G.; Mathieu-Dramard M.; Afenjar A.; Charles P.; Mignot C.; Burglen L.; Van Maldergem L.; Piard J.; Aftimos S.; Mancini G.; Dias P.; Philip N.; Goldenberg A.; Le Merrer M.; Rio M.; Josifova D.; Van Hagen J.M.; Lacombe D.; Edery P.; Dupuis-Girod S.; Putoux A.; Sanlaville D.; Fischer R.; Drevillon L.; Briand-Suleau A.; Metay C.; Goossens M.; Amiel J.; Jacquette A.; Giurgea I.;
Hum. Mutat. 33:64-72(2012)
Cited for: VARIANTS PTHS TRP-565; GLY-572; GLN-572; HIS-574; PRO-574; TRP-576; GLN-576; PRO-578; PRO-583 AND VAL-610;

UniProtKB/Swiss-Prot variant pages

UniProtKB/Swiss-Prot P15884: Variant p.Arg574Pro