NM_001040142.2(SCN2A):c.751G>A (p.Val251Ile) AND Developmental and epileptic encephalopathy, 11

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Oct 23, 2023
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:: RCV001329203.4

Allele description [Variation Report for NM_001040142.2(SCN2A):c.751G>A (p.Val251Ile)]

NM_001040142.2(SCN2A):c.751G>A (p.Val251Ile)

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.751G>A (p.Val251Ile)

HGVS:

NC_000002.12:g.165310376G>A
NG_008143.1:g.75975G>A
NM_001040142.2:c.751G>AMANE SELECT
NM_001040143.2:c.751G>A
NM_001371246.1:c.751G>A
NM_001371247.1:c.751G>A
NM_021007.3:c.751G>A
NP_001035232.1:p.Val251Ile
NP_001035233.1:p.Val251Ile
NP_001358175.1:p.Val251Ile
NP_001358176.1:p.Val251Ile
NP_066287.2:p.Val251Ile
NP_066287.2:p.Val251Ile
NC_000002.11:g.166166886G>A
NM_001040142.2:c.751G>A
NM_021007.2:c.751G>A

Protein change:

V251I

Links:

dbSNP: rs1057519528

NCBI 1000 Genomes Browser:

rs1057519528

Molecular consequence:

NM_001040142.2:c.751G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001040143.2:c.751G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001371246.1:c.751G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001371247.1:c.751G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_021007.3:c.751G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

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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Serrasalmidae 40S ribosomal protein S3a (rps3a) gene, intron.
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001520577	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 9, 2020)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004015156	Cytogenetics and Genomics Lab, Cyprus Institute Of Neurology and Genetics	criteria provided, single submitter (ACGS Guidelines, 2020)	Pathogenic (Jul 17, 2023)	de novo	research	Citation Link,
SCV004046875	Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 23, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001520577

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Apr 9, 2020)

unknown

clinical testing

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

SCV004015156

Cytogenetics and Genomics Lab, Cyprus Institute Of Neurology and Genetics

criteria provided, single submitter

(ACGS Guidelines, 2020)

Pathogenic
(Jul 17, 2023)

de novo

research

Citation Link,

SCV004046875

Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Oct 23, 2023)

unknown

clinical testing

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	de novo	yes	not provided	not provided	not provided	not provided	not provided	research
not provided	unknown	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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 Baylor Genetics, SCV001520577.1

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

Description

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

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

From Cytogenetics and Genomics Lab, Cyprus Institute Of Neurology and Genetics, SCV004015156.1

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

Description

The variant is absent from gnomAD population databases and is located in a mutational hotspot. Alternative variants affecting the same amino at the specific position have previously been determined to be pathogenic while the prevalence of the variant in affected individuals is increased compared with the prevalence in controls. Computational tools also classify this change as moderate pathogenic.

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

From Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, SCV004046875.1

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

Description

This heterozygous mis-sense variant is identified in a 5 year female with neonatal onset seizure from day 3 of life, followed by language delay, recurrent seizure, normal brain MRI, and abnormal EEG. This nucleotide change is absent in gnomAD database [PM2]. Insilico prediction [REVEL=0.72] predicts deleterious nature of this variant [PP3]. A clinvar entry for this variant is available. This variant is submitted to clinvar database [Variation ID: 375510] with “Pathogenic/Likely Pathogenic” interpretation by multiple submitter [PP5]. A different amino acid change, Val251Ala is a known pathogenic variant [PMID:29215089] [PM5]. This is a Mis-sense variant in a gene with low rate of benign miss-ense mutations and for which mis-sense mutation is a common mechanism of a disease [PP2]. Based on the clinical correlation and available evidence, and in absence of parental segregation, this variant is classified as "Likely Pathogenic"

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

Last Updated: Jun 23, 2024

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