ClinVar Miner

Submissions for variant NM_005670.4(EPM2A):c.721C>T (p.Arg241Ter) (rs104893950)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Fulgent Genetics,Fulgent Genetics RCV000003244 SCV000894379 pathogenic Lafora disease 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000187394 SCV000240981 pathogenic not provided 2018-05-17 criteria provided, single submitter clinical testing The R241X variant in the EPM2A gene is found in approximately 40% of individuals with Lafora disease (Gómez-Garre et al., 2000) and has been reported numerous times in association with Lafora disease in patients who have a second pathogenic variant on the opposite allele (Harirchian et al., 2011; Ganesh et al., 2002; Jara-Prado et al., 2014; Salar et al.,2012; Lesca et al., 2010). This variant is predicted to cause loss of normal protein function through protein truncation as the last 91 residues of the protein are lost. The R241X variant is observed in 8/64024 (0.01%) alleles from individuals of European background in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Therefore, we interpret R241X as a pathogenic variant.
GeneReviews RCV000003244 SCV000196904 pathogenic Lafora disease 2015-01-22 no assertion criteria provided literature only
Invitae RCV000703218 SCV000832109 pathogenic Progressive myoclonic epilepsy 2018-12-21 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the EPM2A gene (p.Arg241*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 91 amino acids of the EPM2A protein. This variant is present in population databases (rs104893950, ExAC 0.01%). This variant has been observed in several individuals and several families affected with Lafora’s disease  (PMID: 9771710, 21623095, 25246353). ClinVar contains an entry for this variant (Variation ID: 3098). For these reasons, this variant has been classified as Pathogenic.
Knight Diagnostic Laboratories,Oregon Health and Sciences University RCV000003244 SCV000494241 pathogenic Lafora disease 2016-06-27 criteria provided, single submitter clinical testing The c.721C>T (p.Arg241*) nonsense variant in the EPM2A gene has been previously reported in multiple individuals in more than twenty families affected with Myoclonic Epilepsy of Lafora (Minassian et al., 1998; Harirchian et al., 2011; Ganesh et al., 2002; Jansen and Andermann, 2015). The prevalence of this variant is higher in cases than controls. In addition, multiple pathogenic truncating variants have been reported downstream of this variant. In one individual, it was observed in trans with a known pathogenic variant, Gly279Ser (Minassian et al., 1998). This variant is within the phosphatase catalytic domain and an in vitro functional assay demonstrated that this variant resulted in complete loss of phosphatase activity and glycogen binding capacity (Fernandez-Sanchez et al., 2003). This variant is absent (Exome Sequencing Project, 1000 Genomes) or present at very low frequency in the population databases (ExAC = 0.012%). Multiple in silico algorithms predict this variant to have a deleterious effect (GERP=4.78; CADD = 39; SPIDEX=-3.399). GeneDx has classified this variant as Pathogenic. Therefore, this collective evidence supports the classification of the c.721C>T (p.Arg241*) as a Pathogenic variant for Myoclonic Epilepsy of Lafora. We have confirmed this finding in our laboratory using Sanger sequencing.
OMIM RCV000003244 SCV000023402 pathogenic Lafora disease 2000-12-01 no assertion criteria provided literature only

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