ClinVar Genomic variation as it relates to human health

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.

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

Reported in a child with unspecified developmental delay and no history of seizures (de Kovel et al., 2017); Published functional studies demonstrate a damaging effect as T210M alters protein expression (Kearney et al., 2015); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31600826, 28806457, 29264397, 31513310, 32954514, 33951346)

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

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.

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).

The c.629C>T (p.T210M) alteration is located in exon 2 (coding exon 2) of the KCNB1 gene. This alteration results from a C to T substitution at nucleotide position 629, causing the threonine (T) at amino acid position 210 to be replaced by a methionine (M). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was reported de novo in multiple individuals with features consistent with KCNB1-related developmental and epileptic encephalopathy (de Kovel, 2017; Marini, 2017; Bar 2020; Liu, 2021). Two other reportedly de novo alterations at the same codon, c.629C>G (p.Thr210Arg) and c.629C>A (p.Thr210Lys), have been detected in individuals with developmental delay, language delays, and epilepsy/seizures (Bar, 2020; de Kovel, 2017). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). Functional studies suggest this variant results in a loss of K+ conductance and cell-surface KV2.1 expression, and that the substitution of a methionine would be incompatible with channel function of the S-1 pore interface; however, additional evidence is needed to confirm this finding (Kang, 2019). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

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