VCV000932957.5 - ClinVar

NM_001040142.2(SCN2A):c.4864C>T (p.Pro1622Ser)

Germline

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.

(3)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001040142.2(SCN2A):c.4864C>T (p.Pro1622Ser)

Variation ID: 932957 Accession: VCV000932957.5

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q24.3 2: 165388670 (GRCh38) [ NCBI UCSC ] 2: 166245180 (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	Jul 16, 2020	Feb 28, 2024	Jan 12, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001040142.2:c.4864C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001035232.1:p.Pro1622Ser	missense
NM_001371246.1:c.4864C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001358175.1:p.Pro1622Ser	missense
NM_001040143.2:c.4864C>T	NP_001035233.1:p.Pro1622Ser	missense
NM_001371247.1:c.4864C>T	NP_001358176.1:p.Pro1622Ser	missense
NM_021007.3:c.4864C>T	NP_066287.2:p.Pro1622Ser	missense
NC_000002.12:g.165388670C>T
NC_000002.11:g.166245180C>T
NG_008143.1:g.154269C>T

... more HGVS ... less HGVS

Protein change

Other names

P1622S

Canonical SPDI

NC_000002.12:165388669:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Acceleration of fast inactivation; Functional Epilepsy Nomenclature for Ion Channels [ FENICS-0046]

Increase in slope of activation; Functional Epilepsy Nomenclature for Ion Channels [ FENICS-0035]

Increase in slope of fast inactivation; Functional Epilepsy Nomenclature for Ion Channels [ FENICS-0073]

Mild-moderate slowing of recovery from fast inactivation; Functional Epilepsy Nomenclature for Ion Channels [ FENICS-0056]

Normal peak current; Functional Epilepsy Nomenclature for Ion Channels [ FENICS-0096]

Normal persistent current; Functional Epilepsy Nomenclature for Ion Channels [ FENICS-0044]

Normal slope of activation; Functional Epilepsy Nomenclature for Ion Channels [ FENICS-0036]

Normal voltage dependence of activation; Functional Epilepsy Nomenclature for Ion Channels [ FENICS-0032]

Overall loss-of-function; Functional Epilepsy Nomenclature for Ion Channels [ FENICS-0141]

Severe hyperpolarizing shift of voltage dependence of fast inactivation; Functional Epilepsy Nomenclature for Ion Channels [ FENICS-0069]

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

OMIM: 182390.0018 VarSome

Comment on variant

NCBI staff provided HGVS expressions for allelic variant 182390.0018 by assuming a single nucleotide change.

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	2608	2683

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.
Developmental and epileptic encephalopathy, 11	Pathogenic (1)	no assertion criteria provided	Oct 19, 2020	RCV001200932.3
Complex neurodevelopmental disorder	not provided (1)	no classification provided	-	RCV002319673.1
Developmental and epileptic encephalopathy, 11 Seizures, benign familial infantile, 3	Pathogenic (1)	criteria provided, single submitter	Jan 12, 2024	RCV003770233.2

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.	More information 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.
Pathogenic (Jan 12, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Seizures, benign familial infantile, 3 Developmental and epileptic encephalopathy, 11 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004569194.1 First in ClinVar: Feb 28, 2024 Last updated: Feb 28, 2024	Publications: PubMed (1) PubMed: 28379373 Comment: This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1622 of the SCN2A protein (p.Pro1622Ser). … (more) This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1622 of the SCN2A protein (p.Pro1622Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of SCN2A-related conditions (PMID: 28379373). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 932957). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SCN2A protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SCN2A function (PMID: 28379373). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Oct 19, 2020)	no assertion criteria provided Method: literature only	DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 11 Affected status: not provided Allele origin: germline	OMIM Accession: SCV001371869.2 First in ClinVar: Jul 16, 2020 Last updated: Oct 23, 2020	Publications: PubMed (1) PubMed: 28379373 Comment on evidence: In a 3-year-old child (patient 52) with developmental and epileptic encephalopathy-11 (DEE11; 613721), Wolff et al. (2017) identified a de novo heterozygous pro1622-to-ser (P1622S) substitution … (more) In a 3-year-old child (patient 52) with developmental and epileptic encephalopathy-11 (DEE11; 613721), Wolff et al. (2017) identified a de novo heterozygous pro1622-to-ser (P1622S) substitution in the SCN2A gene. In vitro functional expression studies showed that the mutation resulted in a loss-of-function effect. The most prominent change of the mutant channel was a significant hyperpolarizing shift of the fast inactivation curve, predicting a decrease of channel availability and decreased membrane excitability in neurons compared to wildtype. The patient had onset of intractable myoclonic seizures at 2 years of age. He had moderately impaired development, autism spectrum disorder, ataxia, and microcephaly. Seizure reduction was achieved with topiramate. (less)
not provided (-)	no classification provided Method: literature only	Complex neurodevelopmental disorder Affected status: not applicable Allele origin: not applicable	Channelopathy-Associated Epilepsy Research Center Accession: SCV002605494.1 First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022	Publications: PubMed (1) PubMed: 28379373 Method: whole-cell patch-clamp recording Result: This experiment showed a hyperpolarizing shift of the fast inactivation curve, suggesting overall loss of function.

Comment:

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1622 of the SCN2A protein (p.Pro1622Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of SCN2A-related conditions (PMID: 28379373). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 932957). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SCN2A protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SCN2A function (PMID: 28379373). For these reasons, this variant has been classified as Pathogenic.

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for 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.	More information Help This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Normal peak current (FENICS-0096) Normal persistent current (FENICS-0044) Normal slope of activation (FENICS-0036) Normal voltage dependence of activation (FENICS-0032) Increase in slope of activation (FENICS-0035) Severe hyperpolarizing shift of voltage dependence of fast inactivation (FENICS-0069) Increase in slope of fast inactivation (FENICS-0073) Acceleration of fast inactivation (FENICS-0046) Mild-moderate slowing of recovery from fast inactivation (FENICS-0056) Overall loss-of-function (FENICS-0141)	whole-cell patch-clamp recording	This experiment showed a hyperpolarizing shift of the fast inactivation curve, suggesting overall loss of function.	Channelopathy-Associated Epilepsy Research Center Accession: SCV002605494.1	Publications PubMed (1)

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders.	Wolff M	Brain : a journal of neurology	2017	PMID: 28379373

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_001040142.2(SCN2A):c.4864C>T (p.Pro1622Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...