ClinVar Miner

Submissions for variant NM_005670.4(EPM2A):c.446T>C (p.Ile149Thr) (rs796052430)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000187401 SCV000240988 uncertain significance not provided 2013-10-16 criteria provided, single submitter clinical testing p.Ile149Thr (ATT>ACT): c.446 T>C in exon 2 of the EPM2A gene (NM_005670.3). The Ile149Thr missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a non-conservative amino acid substitution of a non-polar Isoleucine residue with a polar Threonine residue. It alters at a position that is not highly conserved across species; however, other nearby missense mutations (K140N and N148Y) have been reported in association with Lafora disease. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether Ile149Thr is a disease-causing mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).
Invitae RCV000696629 SCV000825197 uncertain significance Progressive myoclonic epilepsy 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 149 of the EPM2A protein (p.Ile149Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with EPM2A-related disease. ClinVar contains an entry for this variant (Variation ID: 205439). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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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