VCV001709240.3 - ClinVar

NM_172107.4(KCNQ2):c.850T>C (p.Tyr284His)

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, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_172107.4(KCNQ2):c.850T>C (p.Tyr284His)

Variation ID: 1709240 Accession: VCV001709240.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 20q13.33 20: 63439675 (GRCh38) [ NCBI UCSC ] 20: 62071028 (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	Oct 15, 2022	Feb 14, 2024	Mar 26, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_172107.4:c.850T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_742105.1:p.Tyr284His	missense
NM_001382235.1:c.850T>C	NP_001369164.1:p.Tyr284His	missense
NM_004518.6:c.850T>C	NP_004509.2:p.Tyr284His	missense
NM_172106.3:c.850T>C	NP_742104.1:p.Tyr284His	missense
NM_172108.5:c.850T>C	NP_742106.1:p.Tyr284His	missense
NM_172109.3:c.850T>C	NP_742107.1:p.Tyr284His	missense
NC_000020.11:g.63439675A>G
NC_000020.10:g.62071028A>G
NG_009004.2:g.37966T>C

... more HGVS ... less HGVS

Protein change

Y284H

Other names

Canonical SPDI

NC_000020.11:63439674:A:G

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

Severe decrease in peak current; Functional Epilepsy Nomenclature for Ion Channels [ FENICS-0087]

Severe hyperpolarizing shift of voltage dependence of activation; Functional Epilepsy Nomenclature for Ion Channels [ FENICS-0031]

Severe slowing of activation; Functional Epilepsy Nomenclature for Ion Channels [ FENICS-0015]

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

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.
KCNQ2		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh38 GRCh37	2156	2287

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, 7	Pathogenic (1)	criteria provided, single submitter	Feb 21, 2022	RCV002289055.2
Early infantile epileptic encephalopathy with suppression bursts	Pathogenic (1)	criteria provided, single submitter	Mar 26, 2023	RCV003588801.2
Complex neurodevelopmental disorder	not provided (1)	no classification provided	-	RCV003315373.1

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 (Feb 21, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Developmental and epileptic encephalopathy, 7 Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002581447.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PS4, PM1, PM5, PM2_SUP, PP3	Number of individuals with the variant: 1 Sex: female
Pathogenic (Mar 26, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Early infantile epileptic encephalopathy with suppression bursts Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004297362.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 27779742‚ 29588952 Comment: For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, … (more) For these reasons, this variant has been classified as Pathogenic. 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 KCNQ2 protein function. ClinVar contains an entry for this variant (Variation ID: 1709240). This missense change has been observed in individual(s) with developmental and epileptic encephalopathy (PMID: 27779742, 29588952). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 284 of the KCNQ2 protein (p.Tyr284His). (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: SCV004015092.1 First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023	Publications: PubMed (1) PubMed: 35104249 Method: whole-cell patch-clamp recording Result: Severe decrease in peak current;Severe slowing of activation;Severe hyperpolarizing shift of voltage dependence of activation

Comment:

For these reasons, this variant has been classified as Pathogenic. 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 KCNQ2 protein function. ClinVar contains an entry for this variant (Variation ID: 1709240). This missense change has been observed in individual(s) with developmental and epileptic encephalopathy (PMID: 27779742, 29588952). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 284 of the KCNQ2 protein (p.Tyr284His).

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.
Severe decrease in peak current (FENICS-0087) Severe slowing of activation (FENICS-0015) Severe hyperpolarizing shift of voltage dependence of activation (FENICS-0031)	whole-cell patch-clamp recording	Severe decrease in peak current;Severe slowing of activation;Severe hyperpolarizing shift of voltage dependence of activation	Channelopathy-Associated Epilepsy Research Center Accession: SCV004015092.1	Publications PubMed (1)

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
High-throughput evaluation of epilepsy-associated KCNQ2 variants reveals functional and pharmacological heterogeneity.	Vanoye CG	JCI insight	2022	PMID: 35104249
Gene panel analysis for nonsyndromic cryptogenic neonatal/infantile epileptic encephalopathy.	Fung CW	Epilepsia open	2017	PMID: 29588952
Gene mutation analysis of 175 Chinese patients with early-onset epileptic encephalopathy.	Zhang Q	Clinical genetics	2017	PMID: 27779742

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_172107.4(KCNQ2):c.850T>C (p.Tyr284His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...