ClinVar Genomic variation as it relates to human health
NM_001165963.4(SCN1A):c.677C>T (p.Thr226Met)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001165963.4(SCN1A):c.677C>T (p.Thr226Met)
Variation ID: 68578 Accession: VCV000068578.33
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q24.3 2: 166052869 (GRCh38) [ NCBI UCSC ] 2: 166909379 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 31, 2013 Oct 8, 2024 Mar 26, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001165963.4:c.677C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001159435.1:p.Thr226Met missense NM_001165964.3:c.677C>T NP_001159436.1:p.Thr226Met missense NM_001202435.3:c.677C>T NP_001189364.1:p.Thr226Met missense NM_001353948.2:c.677C>T NP_001340877.1:p.Thr226Met missense NM_001353949.2:c.677C>T NP_001340878.1:p.Thr226Met missense NM_001353950.2:c.677C>T NP_001340879.1:p.Thr226Met missense NM_001353951.2:c.677C>T NP_001340880.1:p.Thr226Met missense NM_001353952.2:c.677C>T NP_001340881.1:p.Thr226Met missense NM_001353954.2:c.677C>T NP_001340883.1:p.Thr226Met missense NM_001353955.2:c.677C>T NP_001340884.1:p.Thr226Met missense NM_001353957.2:c.677C>T NP_001340886.1:p.Thr226Met missense NM_001353958.2:c.677C>T NP_001340887.1:p.Thr226Met missense NM_001353960.2:c.677C>T NP_001340889.1:p.Thr226Met missense NM_001353961.2:c.-1749C>T 5 prime UTR NM_006920.6:c.677C>T NP_008851.3:p.Thr226Met missense NR_148667.2:n.1063C>T non-coding transcript variant NC_000002.12:g.166052869G>A NC_000002.11:g.166909379G>A NG_011906.1:g.25771C>T LRG_8:g.25771C>T LRG_8t1:c.677C>T P35498:p.Thr226Met - Protein change
- T226M
- Other names
- p.T226M:ACG>ATG
- Canonical SPDI
- NC_000002.12:166052868:G:A
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Functional
consequence HelpThe 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]
- Moderate hyperpolarizing shift of voltage dependence of activation Functional Epilepsy Nomenclature for Ion Channels [FENICS-0030]
- Moderate hyperpolarizing shift of voltage dependence of fast inactivation Functional Epilepsy Nomenclature for Ion Channels [FENICS-0068]
- Moderate slowing of activation Functional Epilepsy Nomenclature for Ion Channels [FENICS-0014]
- Normal peak current Functional Epilepsy Nomenclature for Ion Channels [FENICS-0096]
- Normal rate of recovery from fast inactivation Functional Epilepsy Nomenclature for Ion Channels [FENICS-0054]
- Normal slope of activation Functional Epilepsy Nomenclature for Ion Channels [FENICS-0036]
- Normal slope of fast inactivation Functional Epilepsy Nomenclature for Ion Channels [FENICS-0074]
- Overall mixed or unclear functional effect with respect to biophysical channel activity Functional Epilepsy Nomenclature for Ion Channels [FENICS-0148]
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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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 | ||
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HI score
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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. |
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SCN1A | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
2223 | 4598 |
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. |
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Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Mar 26, 2024 | RCV000059454.8 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Aug 1, 2023 | RCV000188843.20 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 9, 2023 | RCV000558296.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000763460.4 | |
Pathogenic (1) |
no assertion criteria provided
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- | RCV001003956.3 | |
Pathogenic (3) |
criteria provided, single submitter
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Jan 19, 2022 | RCV001420531.7 | |
Pathogenic (1) |
criteria provided, single submitter
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May 21, 2020 | RCV002470755.3 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV003764743.1 |
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. |
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Pathogenic
(Aug 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004033779.10
First in ClinVar: Sep 16, 2023 Last updated: Oct 08, 2024 |
Comment:
SCN1A: PS2, PM2, PM5, PS4:Moderate, PP2, PP3
Number of individuals with the variant: 1
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Pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Generalized epilepsy with febrile seizures plus, type 2
Severe myoclonic epilepsy in infancy Migraine, familial hemiplegic, 3
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000894237.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(Jan 01, 2018)
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criteria provided, single submitter
Method: clinical testing
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Severe myoclonic epilepsy in infancy
Affected status: yes
Allele origin:
de novo
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001335359.1
First in ClinVar: Jun 12, 2020 Last updated: Jun 12, 2020 |
Comment:
This variant was identified as de novo (maternity and paternity confirmed).
Clinical Features:
HP:0011097 (present) , HP:0010864 (present)
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Pathogenic
(Nov 09, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000242473.13
First in ClinVar: Aug 07, 2015 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate a damaging effect (Berecki et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports … (more)
Published functional studies demonstrate a damaging effect (Berecki et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 17347258, 23895530, 21719429, 19585586, 18804930, 25401298, 28794249, 25741868, 30779207, 31791873, 32581362, 31785789, 34489640, 33084218, 31130284, 28252636, 31257984, 31864146) (less)
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Pathogenic
(Jul 09, 2023)
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criteria provided, single submitter
Method: clinical testing
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Early infantile epileptic encephalopathy with suppression bursts
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000633879.5
First in ClinVar: Dec 26, 2017 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 226 of the SCN1A protein (p.Thr226Met). … (more)
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 226 of the SCN1A protein (p.Thr226Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Dravet syndrome and cryptogenic generalized epilepsy (PMID: 17347258, 23895530, 25401298). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 68578). 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 SCN1A protein function. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Severe myoclonic epilepsy in infancy
Generalized epilepsy with febrile seizures plus, type 2
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. (Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV004697320.1
First in ClinVar: Feb 28, 2024 Last updated: Feb 28, 2024 |
Comment:
A heterozygous missense variation in exon 7 of the SCN1A gene that results in the amino acid substitution of Methionine for Threonine at codon 226 … (more)
A heterozygous missense variation in exon 7 of the SCN1A gene that results in the amino acid substitution of Methionine for Threonine at codon 226 was detected. The observed variant c.677C>T (p.Thr226Met) has not been reported in the 1000 genomes and gnomAD databases. The in silico predictions of the variant are damaging by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic. (less)
Age: 0-9 years
Sex: female
Method: DNA was used to perform targeted gene capture using a custom capture kit. Libraries were sequenced to mean >80-100X coverage on Illumina sequencing platform. Sequence obtained were aligned to human references genome using BWA program and analyzed using Picard and GATK-Lite toolkit to identify variants in the targeted genes relevant to clinical indication.
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Pathogenic
(Mar 26, 2024)
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criteria provided, single submitter
Method: clinical testing
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Severe myoclonic epilepsy in infancy
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004807067.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
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Pathogenic
(Jan 19, 2022)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy 6B
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV002072556.2
First in ClinVar: Feb 03, 2022 Last updated: Apr 15, 2024 |
Clinical Features:
Migrating focal seizure (present)
Sex: female
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Pathogenic
(May 21, 2020)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 6
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002768622.2
First in ClinVar: Dec 24, 2022 Last updated: Jul 23, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0200 Variant is predicted to result in a missense … (more)
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0200 Variant is predicted to result in a missense amino acid change from threonine to methionine (exon 5). (N) 0251 Variant is heterozygous. (N) 0107 This gene is known to be associated with autosomal dominant disease. (N) 0301 Variant is absent from gnomAD. (P) 0801 Strong previous evidence of pathogenicity in unrelated individuals (ClinVar; LOVD; Decipher; Berecki, G. et al. (2019)). (P) 0600 Variant is located in an annotated domain or motif (ion transport domain; NCBI, PDB, Decipher). (N) 0501 Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0103 Both loss- and gain-of-function are known mechanisms of disease for this gene (Wei, F. et al. (2017)). (N) 1204 Variant shown to be de novo in proband (parental status not tested but assumed). (P) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign (less)
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Pathogenic
(Mar 01, 2007)
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no assertion criteria provided
Method: literature only
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DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 6B
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV001622834.1
First in ClinVar: May 23, 2021 Last updated: May 23, 2021 |
Comment on evidence:
In 8 unrelated children with developmental and epileptic encephalopathy-6B (DEE6B; 619317), Sadleir et al. (2017) identified a de novo heterozygous c.677C-T transition in exon 5 … (more)
In 8 unrelated children with developmental and epileptic encephalopathy-6B (DEE6B; 619317), Sadleir et al. (2017) identified a de novo heterozygous c.677C-T transition in exon 5 of the SCN1A gene, resulting in a thr226-to-met (T226M) substitution. The mutations were found by whole-exome or targeted sequencing. Functional studies of the variant were not performed, but the authors speculated a gain-of-function effect. The patients had onset of seizures between 6 and 12 weeks of age. Several patients had previously been reported, including patients 3 and 4 who had been reported by Dhamija et al. (2014). Harkin et al. (2007) had identified a de novo heterozygous T226M mutation in the SCN1A gene in a 5-year-old patient (patient 78) with onset of seizures at 2 months of age. The patient had severely impaired intellectual development and increased muscle tone. Another patient (patient 61) also carried the mutation; the latter patient was noted to have severe myoclonic epilepsy of infancy-borderland (SMEB), but clinical details were limited. Functional studies of the variant were not performed. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: research
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Seizure
Global developmental delay
Affected status: yes
Allele origin:
unknown
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NIHR Bioresource Rare Diseases, University of Cambridge
Accession: SCV001161947.1
First in ClinVar: Feb 27, 2020 Last updated: Feb 27, 2020 |
Number of individuals with the variant: 1
Sex: male
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Study: VKGL Data-share Consensus
Accession: SCV001798268.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001930492.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001956265.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Developmental and epileptic encephalopathy 6B
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Accession: SCV002060411.1
First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022 |
Sex: female
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not provided
(-)
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no classification provided
Method: not provided
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Severe myoclonic epilepsy in infancy
Affected status: not provided
Allele origin:
unknown
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UniProtKB/Swiss-Prot
Accession: SCV000090979.1
First in ClinVar: Oct 31, 2013 Last updated: Oct 31, 2013
Comment:
Found in a patiet with A SMEI borderline phenotype and a patient with cryptogenic generalized epilepsy
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not provided
(-)
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no classification provided
Method: literature only
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Severe myoclonic epilepsy in infancy
Affected status: not applicable
Allele origin:
not applicable
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Channelopathy-Associated Epilepsy Research Center
Accession: SCV004809295.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Method: whole-cell patch-clamp recording
Result:
Normal peak current;Moderate hyperpolarizing shift of voltage dependence of activation;Normal slope of activation;Moderate hyperpolarizing shift of voltage dependence of fast inactivation;Normal slope of fast inactivation;Moderate slowing of activation;Acceleration of fast inactivation;Normal rate of recovery from fast inactivation;Overall mixed or unclear functional effect with respect to biophysical channel activity
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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. |
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Normal peak current
Moderate hyperpolarizing shift of voltage dependence of activation
Normal slope of activation
Moderate hyperpolarizing shift of voltage dependence of fast inactivation
Normal slope of fast inactivation
Moderate slowing of activation
Acceleration of fast inactivation
Normal rate of recovery from fast inactivation
Overall mixed or unclear functional effect with respect to biophysical channel activity
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Channelopathy-Associated Epilepsy Research Center
Accession: SCV004809295.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Whole-genome sequencing of patients with rare diseases in a national health system. | Turro E | Nature | 2020 | PMID: 32581362 |
Genotype-phenotype correlation on 45 individuals with West syndrome. | Krey I | European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society | 2020 | PMID: 31791873 |
SCN1A gain of function in early infantile encephalopathy. | Berecki G | Annals of neurology | 2019 | PMID: 30779207 |
Not all SCN1A epileptic encephalopathies are Dravet syndrome: Early profound Thr226Met phenotype. | Sadleir LG | Neurology | 2017 | PMID: 28794249 |
A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy. | Muona M | Nature genetics | 2015 | PMID: 25401298 |
Sleep abnormalities in children with Dravet syndrome. | Dhamija R | Pediatric neurology | 2014 | PMID: 24656210 |
Role of the sodium channel SCN9A in genetic epilepsy with febrile seizures plus and Dravet syndrome. | Mulley JC | Epilepsia | 2013 | PMID: 23895530 |
The spectrum of SCN1A-related infantile epileptic encephalopathies. | Harkin LA | Brain : a journal of neurology | 2007 | PMID: 17347258 |
Text-mined citations for rs121917984 ...
HelpRecord last updated Oct 08, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.