ClinVar Miner

Submissions for variant NM_020822.3(KCNT1):c.675G>A (p.Thr225=) (rs773255063)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000720169 SCV000851046 uncertain significance Seizures 2017-06-15 criteria provided, single submitter clinical testing The c.675G>A variant (also known as p.T225T), located in coding exon 8 of the KCNT1 gene, results from a G to A substitution at nucleotide position 675. This nucleotide substitution does not change the at codon 225. However, this change occurs in the last base pair of coding exon 8, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is poorly conserved in available vertebrate species. Using two different splice site prediction tools, this alteration is predicted by BDGP to abolish the native splice donor site, but is predicted to weaken (but not abolish) the efficiency of the native splice donor site by ESEfinder; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Invitae RCV001051866 SCV001216047 uncertain significance Early infantile epileptic encephalopathy 14; Epilepsy, nocturnal frontal lobe, 5 2020-07-13 criteria provided, single submitter clinical testing This sequence change affects codon 225 of the KCNT1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the KCNT1 protein. This variant also falls at the last nucleotide of exon 8 of the KCNT1 coding sequence, which is part of the consensus splice site for this exon. This variant is present in population databases (rs773255063, ExAC 0.002%). This variant has not been reported in the literature in individuals with KCNT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 589846). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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