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UniProtKB/Swiss-Prot O60741: Variant p.Met305Leu

Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1
Gene: HCN1
Variant information

Variant position:  305
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 Leucine (L) at position 305 (M305L, p.Met305Leu).
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:  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:  Epileptic encephalopathy, early infantile, 24 (EIEE24) [MIM:615871]: A disease characterized by early-onset seizures, intellectual disability of varying degrees, and behavioral disturbances or autistic features in most individuals. {ECO:0000269|PubMed:24747641, ECO:0000269|PubMed:27864847, ECO:0000269|PubMed:30351409}. 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 EIEE24; absence of hyperpolarization-activated currents; highly reduced amount of protein at the cell membrane.
Any additional useful information about the variant.



Sequence information

Variant position:  305
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  890
The length of the canonical sequence.

Location on the sequence:   FHMTYDLASAVVRIFNLIGM  M LLLCHWDGCLQFLVPLLQDF
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                         FHMTYDLASAVVRIFNLIGMMLLLCHWDGCLQFLVPLLQDF

Mouse                         FHMTYDLASAVVRIFNLIGMMLLLCHWDGCLQFLVPLLQDF

Rat                           FHMTYDLASAVVRIFNLIGMMLLLCHWDGCLQFLVPLLQDF

Rabbit                        FHMTYDLASAVVRIFNLIGMMLLLCHWDGCLQFLVPLLQDF

Fission yeast                 LRQTLDSEST-------------------------------

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 – 890 Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1
Transmembrane 296 – 318 Helical; Name=Segment S5
Helix 291 – 321


Literature citations

HCN1 mutation spectrum: from neonatal epileptic encephalopathy to benign generalized epilepsy and beyond.
Marini C.; Porro A.; Rastetter A.; Dalle C.; Rivolta I.; Bauer D.; Oegema R.; Nava C.; Parrini E.; Mei D.; Mercer C.; Dhamija R.; Chambers C.; Coubes C.; Thevenon J.; Kuentz P.; Julia S.; Pasquier L.; Dubourg C.; Carre W.; Rosati A.; Melani F.; Pisano T.; Giardino M.; Innes A.M.; Alembik Y.; Scheidecker S.; Santos M.; Figueiroa S.; Garrido C.; Fusco C.; Frattini D.; Spagnoli C.; Binda A.; Granata T.; Ragona F.; Freri E.; Franceschetti S.; Canafoglia L.; Castellotti B.; Gellera C.; Milanesi R.; Mancardi M.M.; Clark D.R.; Kok F.; Helbig K.L.; Ichikawa S.; Sadler L.; Neupauerova J.; Lassuthova P.; Sterbova K.; Laridon A.; Brilstra E.; Koeleman B.; Lemke J.R.; Zara F.; Striano P.; Soblet J.; Smits G.; Deconinck N.; Barbuti A.; DiFrancesco D.; LeGuern E.; Guerrini R.; Santoro B.; Hamacher K.; Thiel G.; Moroni A.; DiFrancesco J.C.; Depienne C.;
Brain 141:3160-3178(2018)
Cited for: VARIANTS GEFSP10 ALA-85; ARG-171; PRO-172; ARG-243; ILE-260; SER-329; CYS-391; SER-391; MET-414; GLN-590; TYR-680 AND GLY-715; VARIANTS EIEE24 TYR-143; ILE-153; GLU-261; LEU-305; ASP-391; LEU-397 AND PRO-399; CHARACTERIZATION OF VARIANTS EIEE24 ILE-153; LEU-305; ASP-391; LEU-397 AND PRO-399; CHARACTERIZATION OF VARIANTS GEFSP10 ARG-243; SER-329; CYS-391; SER-391; MET-414 AND GLN-590; VARIANTS CYS-264; THR-275 AND ARG-379; INVOLVEMENT IN EIEE24; INVOLVEMENT IN GEFSP10; SUBCELLULAR LOCATION; FUNCTION;

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.