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UniProtKB/Swiss-Prot Q5HYA8: Variant p.Met252Thr

Meckelin
Gene: TMEM67
Variant information

Variant position:  252
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 Methionine (M) to Threonine (T) at position 252 (M252T, p.Met252Thr).
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 medium size and hydrophobic (M) to medium size and polar (T)
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  -1
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:  COACH syndrome (COACHS) [MIM:216360]: A disorder characterized by mental retardation, ataxia due to cerebellar hypoplasia, and hepatic fibrosis. Patients present the molar tooth sign, a midbrain-hindbrain malformation pathognomonic for Joubert syndrome and related disorders. Other features, such as coloboma and renal cysts, may be variable. {ECO:0000269|PubMed:19058225, ECO:0000269|PubMed:19574260, ECO:0000269|PubMed:28860541}. 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.

Involvement in disease:  Joubert syndrome 6 (JBTS6) [MIM:610688]: A disorder presenting with cerebellar ataxia, oculomotor apraxia, hypotonia, neonatal breathing abnormalities and psychomotor delay. Neuroradiologically, it is characterized by cerebellar vermian hypoplasia/aplasia, thickened and reoriented superior cerebellar peduncles, and an abnormally large interpeduncular fossa, giving the appearance of a molar tooth on transaxial slices (molar tooth sign). Additional variable features include retinal dystrophy and renal disease. {ECO:0000269|PubMed:17160906, ECO:0000269|PubMed:19508969, ECO:0000269|PubMed:19574260, ECO:0000269|PubMed:21633164, ECO:0000269|PubMed:26477546}. 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.

Involvement in disease:  Meckel syndrome 3 (MKS3) [MIM:607361]: A disorder characterized by a combination of renal cysts and variably associated features including developmental anomalies of the central nervous system (typically encephalocele), hepatic ductal dysplasia and cysts, and polydactyly. {ECO:0000269|PubMed:16415887, ECO:0000269|PubMed:17185389, ECO:0000269|PubMed:17377820, ECO:0000269|PubMed:19466712, ECO:0000269|PubMed:20232449}. 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 MKS3, JBTS6 and COACHS.
Any additional useful information about the variant.

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



Sequence information

Variant position:  252
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  995
The length of the canonical sequence.

Location on the sequence:   SSAAACWVYANLTSCQALGN  M CVMNMNSYDFATFDACGLFQ
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                         SSAAACWVYANLTSCQALGNMCVMNMNSYDFATFDACGLFQ

Mouse                         ATAAACWTHANLTSCQALGNMCVMNMNSYDSTTLDACRLFH

Rat                           ATAAACWTHSNLTSCQALGNMCVMNMNSYDSTTFDACRLFH

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 36 – 995 Meckelin
Glycosylation 242 – 242 N-linked (GlcNAc...) asparagine


Literature citations

Molecular diagnostics of Meckel-Gruber syndrome highlights phenotypic differences between MKS1 and MKS3.
Consugar M.B.; Kubly V.J.; Lager D.J.; Hommerding C.J.; Wong W.C.; Bakker E.; Gattone V.H. II; Torres V.E.; Breuning M.H.; Harris P.C.;
Hum. Genet. 121:591-599(2007)
Cited for: VARIANTS MKS3 208-ARG--ILE-995 DEL; THR-252; GLN-440; 451-ARG--ILE-995 DEL AND PRO-966;

Mutation spectrum of Meckel syndrome genes: one group of syndromes or several distinct groups?
Tallila J.; Salonen R.; Kohlschmidt N.; Peltonen L.; Kestilae M.;
Hum. Mutat. 30:E813-E830(2009)
Cited for: VARIANTS MKS3 CYS-54; PHE-245; THR-252; CYS-296 GLN-440; CYS-513; ARG-615 AND PRO-966;

Hypomorphic mutations in meckelin (MKS3/TMEM67) cause nephronophthisis with liver fibrosis (NPHP11).
Otto E.A.; Tory K.; Attanasio M.; Zhou W.; Chaki M.; Paruchuri Y.; Wise E.L.; Wolf M.T.F.; Utsch B.; Becker C.; Nuernberg G.; Nuernberg P.; Nayir A.; Saunier S.; Antignac C.; Hildebrandt F.;
J. Med. Genet. 46:663-670(2009)
Cited for: VARIANTS NPHP11 LEU-290; ARG-615; SER-821 AND ARG-821; VARIANTS JBTS6 44-GLN--ILE-995 DEL; 208-ARG--ILE-995 DEL; THR-252; ARG-615; ARG-821 AND THR-833;

Mutations in 3 genes (MKS3, CC2D2A and RPGRIP1L) cause COACH syndrome (Joubert syndrome with congenital hepatic fibrosis).
Doherty D.; Parisi M.A.; Finn L.S.; Gunay-Aygun M.; Al-Mateen M.; Bates D.; Clericuzio C.; Demir H.; Dorschner M.; van Essen A.J.; Gahl W.A.; Gentile M.; Gorden N.T.; Hikida A.; Knutzen D.; Ozyurek H.; Phelps I.; Rosenthal P.; Verloes A.; Weigand H.; Chance P.F.; Dobyns W.B.; Glass I.A.;
J. Med. Genet. 47:8-21(2010)
Cited for: VARIANTS COACHS ASN-99; ARG-130; GLN-172; THR-242; THR-252; VAL-257; SER-349; LEU-358; LYS-372; GLU-376; CYS-441; SER-485; CYS-513; ARG-615; LEU-637; THR-833; PRO-841 AND CYS-942; VARIANTS JBTS6 ARG-82 AND SER-82;

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.