NM_001040142.2(SCN2A):c.4780T>C (p.Trp1594Arg) AND not provided

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Jul 28, 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:: RCV000414096.5

Allele description [Variation Report for NM_001040142.2(SCN2A):c.4780T>C (p.Trp1594Arg)]

NM_001040142.2(SCN2A):c.4780T>C (p.Trp1594Arg)

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.4780T>C (p.Trp1594Arg)

HGVS:

NC_000002.12:g.165386974T>C
NG_008143.1:g.152573T>C
NM_001040142.2:c.4780T>CMANE SELECT
NM_001040143.2:c.4780T>C
NM_001371246.1:c.4780T>C
NM_001371247.1:c.4780T>C
NM_021007.3:c.4780T>C
NP_001035232.1:p.Trp1594Arg
NP_001035233.1:p.Trp1594Arg
NP_001358175.1:p.Trp1594Arg
NP_001358176.1:p.Trp1594Arg
NP_066287.2:p.Trp1594Arg
NP_066287.2:p.Trp1594Arg
NC_000002.11:g.166243484T>C
NM_021007.2:c.4780T>C

Protein change:

W1594R

Links:

dbSNP: rs1057518111

NCBI 1000 Genomes Browser:

rs1057518111

Molecular consequence:

NM_001040142.2:c.4780T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001040143.2:c.4780T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001371246.1:c.4780T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001371247.1:c.4780T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_021007.3:c.4780T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: CN517202

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000491516	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Likely pathogenic (Jun 27, 2016)	germline	clinical testing	Citation Link,
SCV002072147	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 28, 2017)	germline	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

SCV000491516

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Likely pathogenic
(Jun 27, 2016)

germline

clinical testing

Citation Link,

SCV002072147

Genetic Services Laboratory, University of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jul 28, 2017)

germline

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	germline	yes	not provided	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 GeneDx, SCV000491516.1

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

Description

The W1594R variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The W1594R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, this substitution alters a conserved position located within the transmembrane segment S3 of the fourth homologous domain, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, missense variants in nearby residues (Y1589C, G1593R, D1598G) have been reported in the Human Gene Mutation Database in association with SCN2A-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.

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

From Genetic Services Laboratory, University of Chicago, SCV002072147.1

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

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

Last Updated: Apr 9, 2023

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