ClinVar Miner

Submissions for variant NM_020822.3(KCNT1):c.1407C>G (p.His469Gln) (rs537722828)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000520430 SCV000620147 uncertain significance not specified 2017-08-17 criteria provided, single submitter clinical testing The H469Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The H469Q variant is observed in 1/62228 (0.002%) alleles from individuals of European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The H469Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678817 SCV000805003 uncertain significance Hydrocephalus 2017-05-25 criteria provided, single submitter clinical testing
Invitae RCV000707152 SCV000836235 uncertain significance Early infantile epileptic encephalopathy 14; Epilepsy, nocturnal frontal lobe, 5 2018-06-26 criteria provided, single submitter clinical testing This sequence change replaces histidine with glutamine at codon 469 of the KCNT1 protein (p.His469Gln). The histidine residue is moderately conserved and there is a small physicochemical difference between histidine and glutamine. This variant is present in population databases (rs537722828, ExAC 0.002%). This variant has not been reported in the literature in individuals with KCNT1-related disease. ClinVar contains an entry for this variant (Variation ID: 451447). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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