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NM_001040142.2(SCN2A):c.4623C>G (p.Ile1541Met) AND multiple conditions

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Feb 2, 2023
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV003803429.2

Allele description [Variation Report for NM_001040142.2(SCN2A):c.4623C>G (p.Ile1541Met)]

NM_001040142.2(SCN2A):c.4623C>G (p.Ile1541Met)

Gene:
SCN2A:sodium voltage-gated channel alpha subunit 2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2q24.3
Genomic location:
Preferred name:
NM_001040142.2(SCN2A):c.4623C>G (p.Ile1541Met)
HGVS:
  • NC_000002.12:g.165386817C>G
  • NG_008143.1:g.152416C>G
  • NM_001040142.2:c.4623C>GMANE SELECT
  • NM_001040143.2:c.4623C>G
  • NM_001371246.1:c.4623C>G
  • NM_001371247.1:c.4623C>G
  • NM_021007.3:c.4623C>G
  • NP_001035232.1:p.Ile1541Met
  • NP_001035233.1:p.Ile1541Met
  • NP_001358175.1:p.Ile1541Met
  • NP_001358176.1:p.Ile1541Met
  • NP_066287.2:p.Ile1541Met
  • NC_000002.11:g.166243327C>G
Protein change:
I1541M
Molecular consequence:
  • NM_001040142.2:c.4623C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001040143.2:c.4623C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001371246.1:c.4623C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001371247.1:c.4623C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_021007.3:c.4623C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Seizures, benign familial infantile, 3 (BFIS3)
Synonyms:
CONVULSIONS, BENIGN FAMILIAL INFANTILE, 3; Familial neonatal seizures
Identifiers:
MONDO: MONDO:0011904; MedGen: C1843140; Orphanet: 140927; Orphanet: 306; OMIM: 607745
Name:
Developmental and epileptic encephalopathy, 11 (DEE11)
Synonyms:
Early infantile epileptic encephalopathy 11
Identifiers:
MONDO: MONDO:0013388; MedGen: C3150987; Orphanet: 1934; OMIM: 613721

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004592106Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Feb 2, 2023) 		germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Targeted gene panel sequencing in early infantile onset developmental and epileptic encephalopathy.

Na JH, Shin S, Yang D, Kim B, Kim HD, Kim S, Lee JS, Choi JR, Lee ST, Kang HC.

Brain Dev. 2020 Jun;42(6):438-448. doi: 10.1016/j.braindev.2020.02.004. Epub 2020 Mar 2. Erratum in: Brain Dev. 2021 Jan;43(1):179. doi: 10.1016/j.braindev.2020.09.006.

PubMed [citation]
PMID:
32139178

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004592106.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Ile1541 amino acid residue in SCN2A. Other variant(s) that disrupt this residue have been observed in individuals with SCN2A-related conditions (PMID: 32139178), which suggests that this may be a clinically significant amino acid residue. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SCN2A protein function. This missense change has been observed in individual(s) with early infantile epileptic encephalopathy (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1541 of the SCN2A protein (p.Ile1541Met).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024