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

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Dec 14, 2017
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000180879.4

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]

Functional consequence:

Mild decrease in peak current [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0085]
Normal persistent current [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0044]
Normal rate of recovery from fast inactivation [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0054]
Normal voltage dependence of activation [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0032]
Normal voltage dependence of fast inactivation [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0070]
Overall loss-of-function [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0141]

Observations:

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000221848	Center for Bioinformatics, Peking University - University Clinical Cooperation “985 Project” PKU-2014-1-1 See additional submitters Pediatric Department, Peking University First Hospital	criteria provided, single submitter (Xu et al. (Hum Mutat. 2015))	Pathogenic (Dec 20, 2014)	paternal	research	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000996091	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 14, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004809266	Channelopathy-Associated Epilepsy Research Center	no classification provided	not provided	not applicable	literature only	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000221848

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

See additional submitters

criteria provided, single submitter

(Xu et al. (Hum Mutat. 2015))

Pathogenic
(Dec 20, 2014)

paternal

research

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

Citation Link,

SCV000996091

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Dec 14, 2017)

germline

clinical testing

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

SCV004809266

Channelopathy-Associated Epilepsy Research Center

no classification provided

not provided

not applicable

literature only

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	not applicable	not applicable	not provided	not provided	not provided	not provided	not provided	literature only
Chinese	paternal	yes	2	not provided	not provided	not provided	not provided	research

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

See all PubMed Citations (3)

Details of each submission

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

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	paternal	yes	not provided	not provided	not provided		2	not provided	not provided	not provided

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

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical 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.

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

From Channelopathy-Associated Epilepsy Research Center, SCV004809266.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

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

Last Updated: Apr 15, 2024

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