NM_001165963.4(SCN1A):c.4991T>C (p.Met1664Thr) AND Early infantile epileptic encephalopathy with suppression bursts

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: May 15, 2017
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:: RCV000460126.10

Allele description [Variation Report for NM_001165963.4(SCN1A):c.4991T>C (p.Met1664Thr)]

NM_001165963.4(SCN1A):c.4991T>C (p.Met1664Thr)

Genes:

SCN1A:sodium voltage-gated channel alpha subunit 1 [Gene - OMIM - HGNC]
LOC102724058:uncharacterized LOC102724058 [Gene]

Variant type:

single nucleotide variant

Cytogenetic location:

2q24.3

Genomic location:

Preferred name:

NM_001165963.4(SCN1A):c.4991T>C (p.Met1664Thr)

HGVS:

NC_000002.12:g.165992284A>G
NG_011906.1:g.86356T>C
NM_001165963.4:c.4991T>CMANE SELECT
NM_001165964.3:c.4907T>C
NM_001202435.3:c.4991T>C
NM_001353948.2:c.4991T>C
NM_001353949.2:c.4958T>C
NM_001353950.2:c.4958T>C
NM_001353951.2:c.4958T>C
NM_001353952.2:c.4958T>C
NM_001353954.2:c.4955T>C
NM_001353955.2:c.4955T>C
NM_001353957.2:c.4907T>C
NM_001353958.2:c.4907T>C
NM_001353960.2:c.4904T>C
NM_001353961.2:c.2549T>C
NM_006920.6:c.4958T>C
NP_001159435.1:p.Met1664Thr
NP_001159436.1:p.Met1636Thr
NP_001189364.1:p.Met1664Thr
NP_001340877.1:p.Met1664Thr
NP_001340878.1:p.Met1653Thr
NP_001340879.1:p.Met1653Thr
NP_001340880.1:p.Met1653Thr
NP_001340881.1:p.Met1653Thr
NP_001340883.1:p.Met1652Thr
NP_001340884.1:p.Met1652Thr
NP_001340886.1:p.Met1636Thr
NP_001340887.1:p.Met1636Thr
NP_001340889.1:p.Met1635Thr
NP_001340890.1:p.Met850Thr
NP_008851.3:p.Met1653Thr
LRG_8:g.86356T>C
NC_000002.11:g.166848794A>G
NM_001165963.1:c.4991T>C
NR_148667.2:n.5408T>C

Protein change:

M1635T

Links:

dbSNP: rs121918765

NCBI 1000 Genomes Browser:

rs121918765

Molecular consequence:

NM_001165963.4:c.4991T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001165964.3:c.4907T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001202435.3:c.4991T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001353948.2:c.4991T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001353949.2:c.4958T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001353950.2:c.4958T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001353951.2:c.4958T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001353952.2:c.4958T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001353954.2:c.4955T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001353955.2:c.4955T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001353957.2:c.4907T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001353958.2:c.4907T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001353960.2:c.4904T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001353961.2:c.2549T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_006920.6:c.4958T>C - missense variant - [Sequence Ontology: SO:0001583]
NR_148667.2:n.5408T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Early infantile epileptic encephalopathy with suppression bursts (EIEE)
Synonyms:: Early infantile epileptic encephalopathy; Ohtahara syndrome; Developmental and epileptic encephalopathy
Identifiers:: MONDO: MONDO:0100062; MedGen: C0393706; Orphanet: 1934; OMIM: PS308350

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000548766	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (May 15, 2017)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25348405, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000548766

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(May 15, 2017)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

UniProt: a hub for protein information.

UniProt Consortium..

Nucleic Acids Res. 2015 Jan;43(Database issue):D204-12. doi: 10.1093/nar/gku989. Epub 2014 Oct 27.

PubMed [citation]

PMID:: 25348405
PMCID:: PMC4384041

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, SCV000548766.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. This variant is located in an extracellular D4 cytoplasmic domain, a region of the SCN1A protein where several previously reported SCN1A missense mutations are found (PMID: 25348405,¬†18804930) but it is unclear how this variant impacts the function of this protein. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with an SCN1A-related disease. This sequence change replaces methionine with threonine at codon 1664 of the SCN1A protein (p.Met1664Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine. In summary, this variant is a novel missense change that has been shown to arise de novo in an affected individual. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Family studies have indicated that this variant was not present in the parents of an individual with neonatal seizures, which suggests that it was de novo in that affected individual (Invitae).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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