NM_004975.4(KCNB1):c.629C>T (p.Thr210Met) AND Developmental and epileptic encephalopathy, 26

Germline classification:: Pathogenic/Likely pathogenic (7 submissions)
Last evaluated:: Aug 3, 2023
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:: RCV000652424.20

Allele description [Variation Report for NM_004975.4(KCNB1):c.629C>T (p.Thr210Met)]

NM_004975.4(KCNB1):c.629C>T (p.Thr210Met)

Gene:

KCNB1:potassium voltage-gated channel subfamily B member 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

20q13.13

Genomic location:

Preferred name:

NM_004975.4(KCNB1):c.629C>T (p.Thr210Met)

HGVS:

NC_000020.11:g.49374931G>A
NG_041781.2:g.112714C>T
NM_004975.4:c.629C>TMANE SELECT
NP_004966.1:p.Thr210Met
NC_000020.10:g.47991468G>A
NM_004975.2:c.629C>T
NM_004975.3:c.629C>T
p.Thr210Met

Protein change:

T210M

Links:

dbSNP: rs1555889162

NCBI 1000 Genomes Browser:

rs1555889162

Molecular consequence:

NM_004975.4:c.629C>T - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

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

Observations:

Condition(s)

Name:: Developmental and epileptic encephalopathy, 26 (DEE26)
Synonyms:: Epileptic encephalopathy, early infantile, 26
Identifiers:: MONDO: MONDO:0014477; MedGen: C4015119; Orphanet: 442835; OMIM: 616056

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000774294	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 15, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 28806457, 29264397, 28492532
SCV000803684	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	no assertion criteria provided (ACMG Guidelines, 2015)	Pathogenic (Aug 29, 2017)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001132531	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 15, 2018)	germline	research	PubMed (3) [See all records that cite these PMIDs] 29264397, 28252636, 25741868
SCV001523343	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 11, 2019)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002557542	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 2, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 29264397, 31512327, 33951346, 25741868
SCV004023216	Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	criteria provided, single submitter (Hauer et al. (Genet Med. 2018))	Likely pathogenic (Aug 3, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004046111	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	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	1	not provided	not provided	not provided	not provided	clinical testing, research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	de novo	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Neurodevelopmental Disorders Caused by De Novo Variants in KCNB1 Genotypes and Phenotypes.

de Kovel CGF, Syrbe S, Brilstra EH, Verbeek N, Kerr B, Dubbs H, Bayat A, Desai S, Naidu S, Srivastava S, Cagaylan H, Yis U, Saunders C, Rook M, Plugge S, Muhle H, Afawi Z, Klein KM, Jayaraman V, Rajagopalan R, Goldberg E, Marsh E, et al.

JAMA Neurol. 2017 Oct 1;74(10):1228-1236. doi: 10.1001/jamaneurol.2017.1714.

PubMed [citation]

PMID:: 28806457
PMCID:: PMC5710242

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000774294.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This variant disrupts the p.T210 amino acid residue in KCNB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28806457). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 KCNB1 protein function. ClinVar contains an entry for this variant (Variation ID: 542057). This missense change has been observed in individual(s) with KCNB1-related disease (PMID: 29264397; Invitae). 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 threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 210 of the KCNB1 protein (p.Thr210Met).

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

From Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals, SCV000803684.1

#	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	de novo	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001132531.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (3)

Description

The heterozygous p.Thr210Met variant in KCNB1 was identified by our study in one individual with epileptic encephalopathy. Trio exome analysis showed this variant to be de novo in our patient. This variant has also been identified in the literature as de novo in an 8-year old female with epileptic encephalopathy (Marini et al. 2017, PMID: 29264397). Additionally, it was identified in one other case with no additional data (Baldridge et al. 2017, PMID: 28252636). This variant was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic.

#	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 Baylor Genetics, SCV001523343.1

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

Description

This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

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

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002557542.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative, loss of function and gain of function are known mechanisms of disease in this gene and are associated with developmental and epileptic encephalopathy 26 (MIM#616056). However, the ultimate result of each mechanism is channel dysfunction (PMID: 31512327). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from threonine to methionine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants in the ion transport protein domain (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed as de novo in multiple unrelated individuals with developmental and epileptic encephalopathy 26 (MIM#616056) (ClinVar, PMID: 33951346, PMID: 29264397). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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

From Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, SCV004023216.1

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

Description

This variant has been identified by standard clinical testing. Selected ACMG criteria: Likely pathogenic (II):PP5;PP3;PP2;PM2;PS2

#	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		1	not provided	not provided	not provided

From Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego, SCV004046111.1

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

Description

This variant has been previously reported as a de novo change in patients with developmental and epileptic encephalopathy (PMID: 28806457; 29264397). The KCNB1 gene is constrained against variation (Z-score= 4.27 and pLI = 1), and missense variants are a common mechanism of disease (HGMD, ClinVar database). The c.629C>T (p.Thr210Met) variant is absent from the gnomAD population database and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.629C>T (p.Thr210Met) variant is classified as Pathogenic.

#	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: Sep 29, 2024

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