ClinVar Miner

Submissions for variant NM_020822.3(KCNT1):c.2176G>A (p.Asp726Asn) (rs1367605908)

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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 RCV000720407 SCV000851284 uncertain significance Seizures 2016-10-06 criteria provided, single submitter clinical testing The p.D726N variant (also known as c.2176G>A), located in coding exon 19 of the KCNT1 gene, results from a G to A substitution at nucleotide position 2176. The aspartic acid at codon 726 is replaced by asparagine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6481 samples (12962 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Invitae RCV001303412 SCV001492657 uncertain significance Early infantile epileptic encephalopathy 14; Epilepsy, nocturnal frontal lobe, 5 2020-07-26 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 726 of the KCNT1 protein (p.Asp726Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has not been reported in the literature in individuals with KCNT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 589941). 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 KCNT1 protein function. 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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