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UniProtKB/Swiss-Prot A6NHR9: Variant p.Gly137Glu

Structural maintenance of chromosomes flexible hinge domain-containing protein 1
Gene: SMCHD1
Chromosomal location: 18p11.32
Variant information

Variant position:  137
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 Glutamate (E) at position 137 (G137E, p.Gly137Glu).
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 medium size and acidic (E)
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:  Bosma arhinia microphthalmia syndrome (BAMS) [MIM:603457]: An autosomal dominant syndrome characterized by severe hypoplasia of the nose, palatal abnormalities, hypoplasia of the eyes, sensory abnormalities of taste and smell, hypogonadotropic hypogonadism with cryptorchidism, and normal intelligence. {ECO:0000269|PubMed:28067909, ECO:0000269|PubMed:28067911, ECO:0000269|PubMed:29748383}. 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:  Facioscapulohumeral muscular dystrophy 2 (FSHD2) [MIM:158901]: A degenerative muscle disease characterized by slowly progressive weakness of the muscles of the face, upper-arm, and shoulder girdle. The onset of symptoms usually occurs in the first or second decade of life. Affected individuals usually present with impairment of upper extremity elevation. This tends to be followed by facial weakness, primarily involving the orbicularis oris and orbicularis oculi muscles. {ECO:0000269|PubMed:23143600, ECO:0000269|PubMed:24075187, ECO:0000269|PubMed:24128691, ECO:0000269|PubMed:25256356, ECO:0000269|PubMed:25370034, ECO:0000269|PubMed:27059856, ECO:0000269|PubMed:28067911, ECO:0000269|PubMed:29748383}. Note=The disease is caused by mutations affecting the gene represented in this entry. SMCHD1 mutations lead to DUX4 expression in somatic tissues, including muscle cells, when an haplotype on chromosome 4 is permissive for DUX4 expression (PubMed:23143600). Ectopic expression of DUX4 in skeletal muscle activates the expression of stem cell and germline genes, and, when overexpressed in somatic cells, DUX4 can ultimately lead to cell death (PubMed:23143600). FSHD2 and FSHD1 share a common pathophysiological pathway in which the FSHD2 gene SMCHD1 can act as a modifier for disease severity in families affected by FSHD1 (PubMed:24075187, PubMed:25370034). {ECO:0000269|PubMed:23143600, ECO:0000269|PubMed:24075187, ECO:0000269|PubMed:25370034}.
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 BAMS and FSHD2; no change in protein abundance; strongly increased ATPase activity.
Any additional useful information about the variant.

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



Sequence information

Variant position:  137
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  2005
The length of the canonical sequence.

Location on the sequence:   FLPHYDTLVKSGMYEYYASE  G QNPLPFALAELIDNSLSATS
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                         FLPHYDTLVKSGMYEYYASEGQNPLPFALAELIDNSLSATS

Mouse                         FLPHYDTLVKSGMYEYYASEGQNPLPFALAELIDNSLSATS

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 – 2005 Structural maintenance of chromosomes flexible hinge domain-containing protein 1
Region 111 – 702 ATPase activity domain
Alternative sequence 1 – 1065 Missing. In isoform 3.


Literature citations

Inter-individual differences in CpG methylation at D4Z4 correlate with clinical variability in FSHD1 and FSHD2.
Lemmers R.J.; Goeman J.J.; van der Vliet P.J.; van Nieuwenhuizen M.P.; Balog J.; Vos-Versteeg M.; Camano P.; Ramos Arroyo M.A.; Jerico I.; Rogers M.T.; Miller D.G.; Upadhyaya M.; Verschuuren J.J.; Lopez de Munain Arregui A.; van Engelen B.G.; Padberg G.W.; Sacconi S.; Tawil R.; Tapscott S.J.; Bakker B.; van der Maarel S.M.;
Hum. Mol. Genet. 24:659-669(2015)
Cited for: VARIANTS FSHD2 GLU-137; 138-GLN--VAL-2005 DEL; PHE-194; 195-ASN--VAL-2005 DEL; ASP-263; 344-ARG--VAL-2005 DEL; CYS-353; ARG-425; 434-TYR--VAL-2005 DEL; PRO-479; SER-690; SER-716; 731-GLN--VAL-2005 DEL; PRO-748; 780-GLU--VAL-2005 DEL; ASN-849; ASN-868; ILE-1468; SER-1554; 1176-THR-ASP-1177 DELINS MET-HIS; 1795-ARG--VAL-2005 DEL AND 1868-ARG--VAL-2005 DEL;

SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome.
Shaw N.D.; Brand H.; Kupchinsky Z.A.; Bengani H.; Plummer L.; Jones T.I.; Erdin S.; Williamson K.A.; Rainger J.; Stortchevoi A.; Samocha K.; Currall B.B.; Dunican D.S.; Collins R.L.; Willer J.R.; Lek A.; Lek M.; Nassan M.; Pereira S.; Kammin T.; Lucente D.; Silva A.; Seabra C.M.; Chiang C.; An Y.; Ansari M.; Rainger J.K.; Joss S.; Smith J.C.; Lippincott M.F.; Singh S.S.; Patel N.; Jing J.W.; Law J.R.; Ferraro N.; Verloes A.; Rauch A.; Steindl K.; Zweier M.; Scheer I.; Sato D.; Okamoto N.; Jacobsen C.; Tryggestad J.; Chernausek S.; Schimmenti L.A.; Brasseur B.; Cesaretti C.; Garcia-Ortiz J.E.; Buitrago T.P.; Silva O.P.; Hoffman J.D.; Muehlbauer W.; Ruprecht K.W.; Loeys B.L.; Shino M.; Kaindl A.M.; Cho C.H.; Morton C.C.; Meehan R.R.; van Heyningen V.; Liao E.C.; Balasubramanian R.; Hall J.E.; Seminara S.B.; Macarthur D.; Moore S.A.; Yoshiura K.I.; Gusella J.F.; Marsh J.A.; Graham J.M. Jr.; Lin A.E.; Katsanis N.; Jones P.L.; Crowley W.F. Jr.; Davis E.E.; FitzPatrick D.R.; Talkowski M.E.;
Nat. Genet. 49:238-248(2017)
Cited for: INVOLVEMENT IN BAMS; VARIANTS BAMS PRO-107; LYS-129; ASN-135; CYS-135; ILE-135; ASP-136; GLU-137; HIS-139; PHE-141; VAL-171; GLY-242; ARG-345; ARG-348; LEU-400; VAL-420; GLN-473; LYS-523; SER-524 AND GLN-552; CHARACTERIZATION OF VARIANTS BAMS PRO-107; LYS-129; ASN-135; CYS-135; ILE-135; ASP-136; GLU-137; HIS-139; PHE-141; VAL-171; GLY-242; ARG-345; ARG-348; LEU-400; VAL-420; GLN-473; LYS-523; SER-524 AND GLN-552;

FSHD2- and BAMS-associated mutations confer opposing effects on SMCHD1 function.
Gurzau A.D.; Chen K.; Xue S.; Dai W.; Lucet I.S.; Ly T.T.N.; Reversade B.; Blewitt M.E.; Murphy J.M.;
J. Biol. Chem. 293:9841-9853(2018)
Cited for: VARIANTS FSHD2 PHE-194; ASP-263; CYS-283; CYS-353; GLU-478; MET-527 AND SER-690; VARIANTS BAMS ASN-135; GLU-137; SER-342; ARG-348; VAL-420; GLN-473; GLU-518; LYS-523 AND GLN-552; CHARACTERIZATION OF VARIANTS FSHD2 PHE-194; ASP-263; CYS-283; CYS-353; GLU-478; MET-527 AND SER-690; CHARACTERIZATION OF VARIANTS BAMS ASN-135; GLU-137; SER-342; ARG-348; VAL-420; GLN-473; GLU-518; LYS-523 AND GLN-552; FUNCTION; CATALYTIC ACTIVITY;

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.