ClinVar Miner

Submissions for variant NM_001161352.2(KCNMA1):c.1849A>G (p.Thr617Ala)

gnomAD frequency: 0.00002  dbSNP: rs199572642
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001970539 SCV002255833 uncertain significance Generalized epilepsy-paroxysmal dyskinesia syndrome 2021-02-14 criteria provided, single submitter clinical testing This variant is present in population databases (rs199572642, ExAC 0.02%). This variant has not been reported in the literature in individuals with KCNMA1-related conditions. 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. This sequence change replaces threonine with alanine at codon 617 of the KCNMA1 protein (p.Thr617Ala). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and alanine.
Neuberg Centre For Genomic Medicine, NCGM RCV001970539 SCV005382475 uncertain significance Generalized epilepsy-paroxysmal dyskinesia syndrome 2023-05-20 criteria provided, single submitter clinical testing The observed missense c.1849A>G(p.Thr617Ala) variant in KCNMA1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is reported with the allele frequency of 0.002% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Uncertain Significance. However, no details are available for independent assessment. The amino acid Thr at position 617 is changed to a Ala changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Thr617Ala in KCNMA1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Computational evidence (Polyphen - Benign, SIFT - Tolerated, and MutationTaster - Disease causing) predicts conflicting evidence on protein structure and function for this variant. For these reasons, this variant has been classified as Uncertain Significance.

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