ClinVar Genomic variation as it relates to human health
NM_001165963.4(SCN1A):c.3999G>A (p.Met1333Ile)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001165963.4(SCN1A):c.3999G>A (p.Met1333Ile)
Variation ID: 2430161 Accession: VCV002430161.2
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2q24.3 2: 166009722 (GRCh38) [ NCBI UCSC ] 2: 166866232 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Feb 25, 2023 Feb 25, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_001165963.4:c.3999G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001159435.1:p.Met1333Ile missense NM_001165964.3:c.3915G>A NP_001159436.1:p.Met1305Ile missense NM_001202435.3:c.3999G>A NP_001189364.1:p.Met1333Ile missense NM_001353948.2:c.3999G>A NP_001340877.1:p.Met1333Ile missense NM_001353949.2:c.3966G>A NP_001340878.1:p.Met1322Ile missense NM_001353950.2:c.3966G>A NP_001340879.1:p.Met1322Ile missense NM_001353951.2:c.3966G>A NP_001340880.1:p.Met1322Ile missense NM_001353952.2:c.3966G>A NP_001340881.1:p.Met1322Ile missense NM_001353954.2:c.3963G>A NP_001340883.1:p.Met1321Ile missense NM_001353955.2:c.3963G>A NP_001340884.1:p.Met1321Ile missense NM_001353957.2:c.3915G>A NP_001340886.1:p.Met1305Ile missense NM_001353958.2:c.3915G>A NP_001340887.1:p.Met1305Ile missense NM_001353960.2:c.3912G>A NP_001340889.1:p.Met1304Ile missense NM_001353961.2:c.1557G>A NP_001340890.1:p.Met519Ile missense NM_006920.6:c.3966G>A NP_008851.3:p.Met1322Ile missense NR_148667.2:n.4352G>A non-coding transcript variant NC_000002.12:g.166009722C>T NC_000002.11:g.166866232C>T NG_011906.1:g.68918G>A LRG_8:g.68918G>A LRG_8t1:c.3966G>A LRG_8p1:p.Met1322Ile - Protein change
- M1304I, M1305I, M1321I, M1322I, M1333I, M519I
- Other names
- -
- Canonical SPDI
- NC_000002.12:166009721:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
SCN1A | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
2176 | 4518 | |
LOC102724058 | - | - | - | GRCh38 | - | 2288 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
---|---|---|---|---|
Likely pathogenic (1) |
criteria provided, single submitter
|
- | RCV003128167.2 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
---|---|---|---|---|---|
Likely pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Developmental and epileptic encephalopathy 6B
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Lifecell International Pvt. Ltd
Accession: SCV003804180.1
First in ClinVar: Feb 25, 2023 Last updated: Feb 25, 2023 |
Comment:
The missense variant NM_001165963.4 (SCN1A):c.3999G>A (p.Met1333Ile) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Met1333Ile … (more)
The missense variant NM_001165963.4 (SCN1A):c.3999G>A (p.Met1333Ile) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Met1333Ile variant is novel (not in any individuals) in gnomAD. The p.Met1333Ile variant is novel (not in any individuals) in 1kG. There is a small physicochemical difference between methionine and isoleucine. The gene SCN1A has a low rate of benign missense variation as indicated by a high missense variants Z-Score of 5.23. Missense Variants Z-Score is produced by the Exome Aggregation Consortium (60,706 adult humans) by computing a signed Z score for the deviation of observed counts from the expected number. Positive Z scores indicate increased constraint (intolerance to variation) and therefore that the gene had fewer missense variants than expected. (DOI: 10.1038/nature19057). The Missense Badness and MPC scores for this variant is 0.46 and 1.86 respectively. Missense Badness Score is the normalized fold difference of missense substitutions between observed and expected variants from ExAC dataset. This score is then combined with orthogonal deleteriousness metrics into one score called MPC (for Missense badness, PolyPhen-2, and Constraint) designed to classify whether a missense variants is deleterious. Variants with MPC = 2 have a rate nearly 6 times higher in cases than in controls. While those with intermediate MPC values (1 = MPC < 2) have a more modest excess in cases. The gene SCN1A contains 452 pathogenic missense variants, indicating that missense variants are a common mechanism of disease in this gene. The observed variant lies Ion transport protein domain of the SCN1A_HUMAN protein (https://pfam.xfam.org/family/PF00520) and 4 variants within 6 amino acid positions of the variant p.Met1333Ile have been shown to be pathogenic, while none have been shown to be benign. The p.Met1333Ile missense variant is predicted to be damaging by both SIFT and PolyPhen2. The methionine residue at codon 1333 of SCN1A is conserved in all mammalian species. The nucleotide c.3999 in SCN1A is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. (less)
Ethnicity/Population group: Asian
Geographic origin: India
|
Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpThere are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar. |
Text-mined citations for this variant ...
HelpRecord last updated May 07, 2023
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.