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UniProtKB/Swiss-Prot Q9Y3Z3: Variant p.Met385Val

Deoxynucleoside triphosphate triphosphohydrolase SAMHD1
Gene: SAMHD1
Variant information

Variant position:  385
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 Valine (V) at position 385 (M385V, p.Met385Val).
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:  Similar physico-chemical property. Both residues are medium size and hydrophobic.
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:  Aicardi-Goutieres syndrome 5 (AGS5) [MIM:612952]: A form of Aicardi-Goutieres syndrome, a genetically heterogeneous disease characterized by cerebral atrophy, leukoencephalopathy, intracranial calcifications, chronic cerebrospinal fluid (CSF) lymphocytosis, increased CSF alpha-interferon, and negative serologic investigations for common prenatal infection. Clinical features as thrombocytopenia, hepatosplenomegaly and elevated hepatic transaminases along with intermittent fever may erroneously suggest an infective process. Severe neurological dysfunctions manifest in infancy as progressive microcephaly, spasticity, dystonic posturing and profound psychomotor retardation. Death often occurs in early childhood. {ECO:0000269|PubMed:19525956, ECO:0000269|PubMed:20131292, ECO:0000269|PubMed:20842748, ECO:0000269|PubMed:24035396, ECO:0000269|PubMed:24183309, ECO:0000269|PubMed:28229507, ECO:0000269|PubMed:29670289}. 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 AGS5; loss of function in defense response to virus; loss of oligomerization.
Any additional useful information about the variant.

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

Sequence information

Variant position:  385
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  626
The length of the canonical sequence.

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.







Slime mold                    TRYSLHKLVYTHKVGKSIEFMIADAFTEADQFLK-------

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.

Chain 1 – 626 Deoxynucleoside triphosphate triphosphohydrolase SAMHD1
Binding site 366 – 366 Substrate
Binding site 376 – 376 dNTP; shared with neighboring subunit
Binding site 377 – 377 dNTP; shared with neighboring subunit
Mutagenesis 366 – 366 R -> A. Abolishes dNTPase activity; when associated with A-312 and A-315.
Mutagenesis 370 – 370 H -> A. Abolishes dNTPase activity; when associated with G-374.
Mutagenesis 372 – 372 R -> D. Abolished homotetramerization and dNTPase activity.
Mutagenesis 374 – 374 Y -> G. Abolishes dNTPase activity; when associated with A-370.
Mutagenesis 375 – 375 Q -> A. Abolished dNTPase activity without affecting homotetramerization.
Mutagenesis 376 – 376 H -> A. Impairs homotetramerization and abolishes dNTPase activity; when associated with A-352 and A-377.
Mutagenesis 377 – 377 K -> A. Impairs homotetramerization and abolishes dNTPase activity; when associated with A-352 and A-376.
Helix 377 – 393

Literature citations

A SAMHD1 mutation associated with Aicardi-Goutieres Syndrome uncouples the ability of SAMHD1 to restrict HIV-1 from its ability to downmodulate type I interferon in humans.
White T.E.; Brandariz-Nunez A.; Martinez-Lopez A.; Knowlton C.; Lenzi G.; Kim B.; Ivanov D.; Diaz-Griffero F.;
Hum. Mutat. 38:658-668(2017)

Mutations involved in Aicardi-Goutieres syndrome implicate SAMHD1 as regulator of the innate immune response.
Rice G.I.; Bond J.; Asipu A.; Brunette R.L.; Manfield I.W.; Carr I.M.; Fuller J.C.; Jackson R.M.; Lamb T.; Briggs T.A.; Ali M.; Gornall H.; Couthard L.R.; Aeby A.; Attard-Montalto S.P.; Bertini E.; Bodemer C.; Brockmann K.; Brueton L.A.; Corry P.C.; Desguerre I.; Fazzi E.; Cazorla A.G.; Gener B.; Hamel B.C.J.; Heiberg A.; Hunter M.; van der Knaap M.S.; Kumar R.; Lagae L.; Landrieu P.G.; Lourenco C.M.; Marom D.; McDermott M.F.; van der Merwe W.; Orcesi S.; Prendiville J.S.; Rasmussen M.; Shalev S.A.; Soler D.M.; Shinawi M.; Spiegel R.; Tan T.Y.; Vanderver A.; Wakeling E.L.; Wassmer E.; Whittaker E.; Lebon P.; Stetson D.B.; Bonthron D.T.; Crow Y.J.;
Nat. Genet. 41:829-832(2009)
Cited for: VARIANTS AGS5 PRO-123; CYS-143; HIS-143; GLN-145; ASN-201; SER-209; VAL-254; SER-369 AND VAL-385; FUNCTION; SUBCELLULAR LOCATION;

Assessment of interferon-related biomarkers in Aicardi-Goutieres syndrome associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR: a case-control study.
Rice G.I.; Forte G.M.; Szynkiewicz M.; Chase D.S.; Aeby A.; Abdel-Hamid M.S.; Ackroyd S.; Allcock R.; Bailey K.M.; Balottin U.; Barnerias C.; Bernard G.; Bodemer C.; Botella M.P.; Cereda C.; Chandler K.E.; Dabydeen L.; Dale R.C.; De Laet C.; De Goede C.G.; Del Toro M.; Effat L.; Enamorado N.N.; Fazzi E.; Gener B.; Haldre M.; Lin J.P.; Livingston J.H.; Lourenco C.M.; Marques W. Jr.; Oades P.; Peterson P.; Rasmussen M.; Roubertie A.; Schmidt J.L.; Shalev S.A.; Simon R.; Spiegel R.; Swoboda K.J.; Temtamy S.A.; Vassallo G.; Vilain C.N.; Vogt J.; Wermenbol V.; Whitehouse W.P.; Soler D.; Olivieri I.; Orcesi S.; Aglan M.S.; Zaki M.S.; Abdel-Salam G.M.; Vanderver A.; Kisand K.; Rozenberg F.; Lebon P.; Crow Y.J.;
Lancet Neurol. 12:1159-1169(2013)
Cited for: VARIANTS AGS5 120-ASP--HIS-123 DEL; PRO-123; HIS-143; ASN-201; VAL-254; VAL-385 AND THR-448;

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.