VCV000206996.9 - ClinVar

NM_001040142.2(SCN2A):c.4025T>C (p.Leu1342Pro)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic/Likely pathogenic

2 out of 4 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Functional data are available for this variant

Variant Details

Identifiers

NM_001040142.2(SCN2A):c.4025T>C (p.Leu1342Pro)

Variation ID: 206996 Accession: VCV000206996.9

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q24.3 2: 165374737 (GRCh38) [ NCBI UCSC ] 2: 166231247 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Aug 7, 2015	Mar 19, 2022	Jan 21, 2019

HGVS

Nucleotide	Protein	Molecular consequence
NM_001040142.2:c.4025T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001035232.1:p.Leu1342Pro	missense
NM_001371246.1:c.4025T>C MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001358175.1:p.Leu1342Pro	missense
NM_001040143.2:c.4025T>C	NP_001035233.1:p.Leu1342Pro	missense
NM_001371247.1:c.4025T>C	NP_001358176.1:p.Leu1342Pro	missense
NM_021007.3:c.4025T>C	NP_066287.2:p.Leu1342Pro	missense
NC_000002.12:g.165374737T>C
NC_000002.11:g.166231247T>C
NG_008143.1:g.140336T>C

... more HGVS ... less HGVS

Protein change

L1342P

Other names

p.L1342P:CTG>CCG

Canonical SPDI

NC_000002.12:165374736:T:C

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA317954 dbSNP: rs796053134 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
SCN2A		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	3008	3084

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Likely pathogenic (1)	criteria provided, single submitter	Sep 11, 2012	RCV000189147.1
Developmental and epileptic encephalopathy, 11	Pathogenic (1)	criteria provided, single submitter	Jan 21, 2019	RCV001252986.1
West syndrome	Pathogenic (1)	no assertion criteria provided	Feb 16, 2022	RCV001847841.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	Expand all rows Collapse all rows Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Sep 11, 2012) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification (06012015))	not provided	GeneDx Accession: SCV000242779.10 First in ClinVar: Aug 07, 2015 Last updated: Aug 07, 2015	Comment: show p.Leu1342Pro (CTG>CCG):c.4025 T>C in exon 22 of the SCN2A gene (NM_021007.2). The Leu1342Pro missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI ESP Exome Variant Project has not identified Leu1342Pro in approximately 6,500 individuals of European or African American ethnicity, indicating that it is not a common benign variant in these populations. Although Leucine and Proline are both uncharged, non-polar amino acids, the gain of a bulky Proline residue could alter the secondary structure of the protein. Leu1342Pro alters a highly conserved position in the S5 segment of the third transmembrane domain, and multiple in silico algorithms predict it is damaging to protein structure/function. Therefore, based on the currently available information, Leu1342Pro is a strong candidate for a disease-causing mutation, although the possibility that it is a benign variant cannot be excluded. The variant is found in INFANT-EPI panel(s). (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Jan 21, 2019) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Developmental and epileptic encephalopathy, 11	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001428474.1 First in ClinVar: Aug 16, 2020 Last updated: Aug 16, 2020	Comment: show This variant was identified as de novo (maternity and paternity confirmed). (less) Observation: 1 Collection method: clinical testing Allele origin: de novo Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: de novo Affected status: yes Number of individuals with the variant: 1

Pathogenic (Feb 16, 2022) N Not contributing to aggregate classification	no assertion criteria provided		Neurology Department, Shenzhen Children's Hospital Accession: SCV002099481.1 First in ClinVar: Mar 19, 2022 Last updated: Mar 19, 2022	Observation: 1 Collection method: clinical testing Allele origin: de novo Affected status: yes Observation 1 Collection method: clinical testing Allele origin: de novo Affected status: yes

Comment:

p.Leu1342Pro (CTG>CCG):c.4025 T>C in exon 22 of the SCN2A gene (NM_021007.2). The Leu1342Pro missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI ESP Exome Variant Project has not identified Leu1342Pro in approximately 6,500 individuals of European or African American ethnicity, indicating that it is not a common benign variant in these populations. Although Leucine and Proline are both uncharged, non-polar amino acids, the gain of a bulky Proline residue could alter the secondary structure of the protein. Leu1342Pro alters a highly conserved position in the S5 segment of the third transmembrane domain, and multiple in silico algorithms predict it is damaging to protein structure/function. Therefore, based on the currently available information, Leu1342Pro is a strong candidate for a disease-causing mutation, although the possibility that it is a benign variant cannot be excluded. The variant is found in INFANT-EPI panel(s).

Citations for germline classification of this variant

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Submissions - Functional Data

not provided -- Severe hyperpolarizing shift of voltage dependence of fast inactivation, Severe hyperpolarizing shift of voltage dependence of activation, Slowing of recovery from fast inactivation, Normal slope of activation, Normal slope of fast inactivation, Normal peak current, Effect on use dependence, Overall mixed or unclear functional effect not able to be clearly categorized as Gain- or Loss-of-Function

assessed by not provided

Result:

This experiment showed severe hyperpolarizing shift of voltage dependence of fast inactivation, severe hyperpolarizing shift of voltage dependence of activation, and deceleration or slowing of recovery from fast inactivation. Overall mixed or unclear functional effect not able to be clearly categorized as Gain- or Loss-of-Function

Channelopathy-Associated Epilepsy Research Center

Accession: SCV002605510.2

Submitted: 2022-10-25

Assay description:

whole-cell patch-clamp recording

Disease context: Complex neurodevelopmental disorder
Transcript: NM_021007.2:c.4025T>C
Molecular phenotype measured: not provided
Cell line: HEK293T cells
Collection method: literature only
Species: Human

Text-mined citations for rs796053134 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Apr 13, 2026