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UniProtKB/Swiss-Prot P35498: Variant p.Met976Ile

Sodium channel protein type 1 subunit alpha
Gene: SCN1A
Variant information

Variant position:  976
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 Isoleucine (I) at position 976 (M976I, p.Met976Ile).
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:  Generalized epilepsy with febrile seizures plus 2 (GEFS+2) [MIM:604403]: A rare autosomal dominant, familial condition with incomplete penetrance and large intrafamilial variability. Patients display febrile seizures persisting sometimes beyond the age of 6 years and/or a variety of afebrile seizure types. This disease combines febrile seizures, generalized seizures often precipitated by fever at age 6 years or more, and partial seizures, with a variable degree of severity. {ECO:0000269|PubMed:10742094, ECO:0000269|PubMed:11254444, ECO:0000269|PubMed:11254445, ECO:0000269|PubMed:11524484, ECO:0000269|PubMed:11756608, ECO:0000269|PubMed:12535936, ECO:0000269|PubMed:12576172, ECO:0000269|PubMed:12919402, ECO:0000269|PubMed:14672992, ECO:0000269|PubMed:15525788, ECO:0000269|PubMed:15694566, ECO:0000269|PubMed:15715999, ECO:0000269|PubMed:16525050, ECO:0000269|PubMed:17347258, ECO:0000269|PubMed:17507202, ECO:0000269|PubMed:17561957, ECO:0000269|PubMed:17927801, ECO:0000269|PubMed:17928445, ECO:0000269|PubMed:18251839, ECO:0000269|PubMed:18413471, ECO:0000269|PubMed:18566737, ECO:0000269|PubMed:19339291, ECO:0000269|PubMed:19464195, ECO:0000269|PubMed:19522081, ECO:0000269|PubMed:20117752, ECO:0000269|PubMed:20550552, ECO:0000269|PubMed:20600615, ECO:0000269|PubMed:20729507, ECO:0000269|PubMed:21248271, ECO:0000269|PubMed:21864321}. 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:  Epileptic encephalopathy, early infantile, 6 (EIEE6) [MIM:607208]: A severe form of epileptic encephalopathy characterized by generalized tonic, clonic, and tonic-clonic seizures that are initially induced by fever and begin during the first year of life. Later, patients also manifest other seizure types, including absence, myoclonic, and simple and complex partial seizures. Psychomotor development delay is observed around the second year of life. Some patients manifest a borderline disease phenotype and do not necessarily fulfill all diagnostic criteria for core EIEE6. EIEE6 is considered to be the most severe phenotype within the spectrum of generalized epilepsies with febrile seizures-plus. {ECO:0000269|PubMed:11359211, ECO:0000269|PubMed:12083760, ECO:0000269|PubMed:12566275, ECO:0000269|PubMed:12754708, ECO:0000269|PubMed:12821740, ECO:0000269|PubMed:14504318, ECO:0000269|PubMed:14672992, ECO:0000269|PubMed:14738421, ECO:0000269|PubMed:15087100, ECO:0000269|PubMed:15944908, ECO:0000269|PubMed:16122630, ECO:0000269|PubMed:16458823, ECO:0000269|PubMed:16713920, ECO:0000269|PubMed:17054684, ECO:0000269|PubMed:17054685, ECO:0000269|PubMed:17129991, ECO:0000269|PubMed:17347258, ECO:0000269|PubMed:17561957, ECO:0000269|PubMed:18413471, ECO:0000269|PubMed:18639757, ECO:0000269|PubMed:18930999, ECO:0000269|PubMed:19522081, ECO:0000269|PubMed:19563458, ECO:0000269|PubMed:19589774, ECO:0000269|PubMed:19783390, ECO:0000269|PubMed:20110217, ECO:0000269|PubMed:20431604, ECO:0000269|PubMed:20452746, ECO:0000269|PubMed:20522430, ECO:0000269|PubMed:20729507, ECO:0000269|PubMed:21248271, ECO:0000269|PubMed:21864321, ECO:0000269|PubMed:22092154, ECO:0000269|PubMed:22612257, ECO:0000269|PubMed:23195492, ECO:0000269|PubMed:23662938, ECO:0000269|PubMed:23708187, ECO:0000269|PubMed:25818041, ECO:0000269|PubMed:26993267, ECO:0000269|PubMed:27864847, ECO:0000269|PubMed:28544625}. 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 EIEE6 and GEFS+2.
Any additional useful information about the variant.



Sequence information

Variant position:  976
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  2009
The length of the canonical sequence.

Location on the sequence:   MWDCMEVAGQAMCLTVFMMV  M VIGNLVVLNLFLALLLSSFS
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                         MWDCMEVAGQAMCLTVFMMVMVIGNLVVLNLFLALLLSSFS

Mouse                         MWDCMEVAGQAMCLTVFMMVMVIGNLVVLNLFLALLLSSFS

Rat                           MWDCMEVAGQAMCLTVFMMVMVIRNLVVLNLFLALLLSSFS

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 1 – 2009 Sodium channel protein type 1 subunit alpha
Transmembrane 971 – 991 Helical; Name=S6 of repeat II
Repeat 750 – 1022 II


Literature citations

Mutational analysis of the SCN1A, SCN1B and GABRG2 genes in 150 Italian patients with idiopathic childhood epilepsies.
Orrico A.; Galli L.; Grosso S.; Buoni S.; Pianigiani R.; Balestri P.; Sorrentino V.;
Clin. Genet. 75:579-581(2009)
Cited for: VARIANTS GLN-542 AND PHE-790; VARIANT FEB3A ASP-1308; VARIANT EIEE6 CYS-1648; VARIANTS GEFS+2 THR-899; ILE-976; ASN-1249 AND MET-1250; POSSIBLE INVOLVEMENT IN PANAYIOTOPOULOS SYNDROME;

Genotype-phenotype associations in SCN1A-related epilepsies.
Zuberi S.M.; Brunklaus A.; Birch R.; Reavey E.; Duncan J.; Forbes G.H.;
Neurology 76:594-600(2011)
Cited for: VARIANTS EIEE6 PHE-17 DEL; THR-68; ASN-79; CYS-84; PRO-98; GLN-101; TRP-101; ARG-108; ASP-127; ARG-199; SER-227; THR-227; SER-232; ARG-233; VAL-342; ASP-343; TRP-351; SER-359; ARG-363; ARG-384; CYS-393; HIS-393; VAL-400; VAL-403; PHE-406; GLY-626; ASP-762; THR-785; ILE-812; ARG-842; 854-GLY-LEU-855 DEL; CYS-859; GLN-862; PRO-890; CYS-932; PRO-933; CYS-946; HIS-946; ARG-950; LYS-954; LYS-956; LEU-957; ILE-976; VAL-979; ARG-993; 999-ASN-LEU-1000 DELINS LEU-ILE-SER; LYS-1208; LYS-1221; PHE-1230; ASP-1238; ALA-1266; ASN-1288; VAL-1320; PRO-1326; GLY-1350; ARG-1358; PRO-1370; HIS-1378; THR-1378; ILE-1394; TYR-1396; SER-1417; PHE-1423; ALA-1429 DEL; VAL-1433; LYS-1450; SER-1451; LYS-1454; HIS-1462; LYS-1476; LYS-1503; GLY-1544; GLU-1586; ARG-1588; HIS-1592; PRO-1592; SER-1605; GLU-1637; THR-1638; CYS-1648; GLU-1653; PRO-1660; PRO-1667; LEU-1668; ILE-1672; THR-1673; THR-1683; ASP-1684; TRP-1688; ARG-1714; ASN-1763; ASN-1770; PHE-1770; THR-1770; THR-1780; VAL-1783; LYS-1787; PRO-1832; LYS-1852; LEU-1855; GLU-1880; THR-1909 DEL AND ARG-1927 DELINS ILE-ILE-GLN; VARIANTS GEFS+2 LEU-218; ILE-254; GLY-291; THR-960; VAL-973; SER-1204; PHE-1230; ASP-1414; HIS-1596; LEU-1739 AND THR-1867; VARIANTS ASN-45; VAL-333; ASN-382; HIS-604; ILE-699; THR-924; HIS-931; GLU-1006; ILE-1079; THR-1109; ASP-1308; ASP-1326; MET-1483 AND PHE-1683;

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.