NM_001165963.4(SCN1A):c.5555T>C (p.Met1852Thr) AND Severe myoclonic epilepsy in infancy

Clinical significance:Pathogenic (Last evaluated: Dec 14, 2017)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000180879.2

Allele description [Variation Report for NM_001165963.4(SCN1A):c.5555T>C (p.Met1852Thr)]

NM_001165963.4(SCN1A):c.5555T>C (p.Met1852Thr)

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.5555T>C (p.Met1852Thr)
HGVS:
  • NC_000002.12:g.165991720A>G
  • NG_011906.1:g.86920T>C
  • NM_001165963.4:c.5555T>CMANE SELECT
  • NM_001165964.3:c.5471T>C
  • NM_001202435.3:c.5555T>C
  • NM_001353948.2:c.5555T>C
  • NM_001353949.2:c.5522T>C
  • NM_001353950.2:c.5522T>C
  • NM_001353951.2:c.5522T>C
  • NM_001353952.2:c.5522T>C
  • NM_001353954.2:c.5519T>C
  • NM_001353955.2:c.5519T>C
  • NM_001353957.2:c.5471T>C
  • NM_001353958.2:c.5471T>C
  • NM_001353960.2:c.5468T>C
  • NM_001353961.2:c.3113T>C
  • NM_006920.6:c.5522T>C
  • NP_001159435.1:p.Met1852Thr
  • NP_001159436.1:p.Met1824Thr
  • NP_001189364.1:p.Met1852Thr
  • NP_001340877.1:p.Met1852Thr
  • NP_001340878.1:p.Met1841Thr
  • NP_001340879.1:p.Met1841Thr
  • NP_001340880.1:p.Met1841Thr
  • NP_001340881.1:p.Met1841Thr
  • NP_001340883.1:p.Met1840Thr
  • NP_001340884.1:p.Met1840Thr
  • NP_001340886.1:p.Met1824Thr
  • NP_001340887.1:p.Met1824Thr
  • NP_001340889.1:p.Met1823Thr
  • NP_001340890.1:p.Met1038Thr
  • NP_008851.3:p.Met1841Thr
  • LRG_8t1:c.5522T>C
  • LRG_8:g.86920T>C
  • NC_000002.11:g.166848230A>G
  • NM_001165963.1:c.5555T>C
  • NM_006920.4:c.5522T>C
  • NR_148667.2:n.5972T>C
Protein change:
M1038T
Links:
UniProtKB/Swiss-Prot: VAR_029727; dbSNP: rs121918783
NCBI 1000 Genomes Browser:
rs121918783
Molecular consequence:
  • NM_001165963.4:c.5555T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001165964.3:c.5471T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001202435.3:c.5555T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001353948.2:c.5555T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001353949.2:c.5522T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001353950.2:c.5522T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001353951.2:c.5522T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001353952.2:c.5522T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001353954.2:c.5519T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001353955.2:c.5519T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001353957.2:c.5471T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001353958.2:c.5471T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001353960.2:c.5468T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001353961.2:c.3113T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_006920.6:c.5522T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NR_148667.2:n.5972T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
Observations:
1

Condition(s)

Name:
Severe myoclonic epilepsy in infancy (DRVT)
Synonyms:
Epilepsy, Myoclonic, Infantile, Severe; Dravet syndrome; Epileptic encephalopathy, early infantile, 6 (Dravet syndrome)
Identifiers:
MONDO: MONDO:0100135; MedGen: C0751122; Orphanet: 33069; OMIM: 607208

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000221848Center for Bioinformatics, Peking University - University Clinical Cooperation “985 Project” PKU-2014-1-1

See additional submitters

criteria provided, single submitter
Pathogenic
(Dec 20, 2014)
paternalresearch

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV000996091Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diegocriteria provided, single submitter
Pathogenic
(Dec 14, 2017)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Description

Dravet syndrome (DS) probands were recruited from the outpatient and inpatient child neurology units of Peking University First Hospital from 2005 till present. The study was approved by the Ethics Committee of Peking University First Hospital and the Institutional Review Board at Peking University. Participants or their parents provided written informed consent before enrollment. We collected a total of 267 mutations from 255 families with probands diagnosed with DS in China. All probands fulfilled the clinical diagnostic criteria.

SCV000221848

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes1not providednot provided1not providedclinical testing
Chinesepaternalyes2not providednot providednot providednot providedresearch

Citations

PubMed

Amplicon Resequencing Identified Parental Mosaicism for Approximately 10% of "de novo" SCN1A Mutations in Children with Dravet Syndrome.

Xu X, Yang X, Wu Q, Liu A, Yang X, Ye AY, Huang AY, Li J, Wang M, Yu Z, Wang S, Zhang Z, Wu X, Wei L, Zhang Y.

Hum Mutat. 2015 Sep;36(9):861-72. doi: 10.1002/humu.22819. Epub 2015 Jul 24.

PubMed [citation]
PMID:
26096185
PMCID:
PMC5034833

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Center for Bioinformatics, Peking University - University Clinical Cooperation “985 Project” PKU-2014-1-1, SCV000221848.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1Chinese2not providednot providedresearch PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1paternalyesnot providednot providednot provided2not providednot providednot provided

From Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego, SCV000996091.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)

Description

This variant has been previously reported as disease causing in a patient with severe myoclonic epilepsy in infancy and in the patient's sibling with generalized epilepsy with febrile seizures (PMID: 12919402) and in an individual with Dravet syndrome (PMID: 26096185). The c.5555T>C (p.Met1852Thr) variant is absent from population databases, thus is presumed to be rare. Functional studies show that this change is a loss of function variant, specifically affecting cellular trafficking (PMID: 17928445). In silico algorithms predict this change to be deleterious. Based on the overall evidence the c.5555T>C (p.Met1852Thr) variant is classified as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes1not providednot provided1not providednot providednot provided

Last Updated: Oct 7, 2021

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