rs104893950

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_StrongPP5_Very_Strong

The NM_005670.4(EPM2A):c.721C>T(p.Arg241*) variant causes a stop gained, splice region change. The variant allele was found at a frequency of 0.000108 in 1,613,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

EPM2A
NM_005670.4 stop_gained, splice_region

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:14O:1

Conservation

PhyloP100: 5.66

Publications

29 publications found

Variant links:

Genes affected

EPM2A (HGNC:3413): (EPM2A glucan phosphatase, laforin) This gene encodes a dual-specificity phosphatase and may be involved in the regulation of glycogen metabolism. The protein acts on complex carbohydrates to prevent glycogen hyperphosphorylation, thus avoiding the formation of insoluble aggregates. Loss-of-function mutations in this gene have been associated with Lafora disease, a rare, adult-onset recessive neurodegenerative disease, which results in myoclonus epilepsy and usually results in death several years after the onset of symptoms. The disease is characterized by the accumulation of insoluble particles called Lafora bodies, which are derived from glycogen. [provided by RefSeq, Jan 2018]

EPM2A Gene-Disease associations (from GenCC):

Lafora disease
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, PanelApp Australia

EPM2A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 15 pathogenic variants in the truncated region.

PP5

Variant 6-145627691-G-A is Pathogenic according to our data. Variant chr6-145627691-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 3098.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPM2A	NM_005670.4 link	c.721C>T	p.Arg241*	stop_gained, splice_region_variant	Exon 4 of 4	ENST00000367519.9	NP_005661.1	O95278-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPM2A	ENST00000367519.9 link	c.721C>T	p.Arg241*	stop_gained, splice_region_variant	Exon 4 of 4	1	NM_005670.4	ENSP00000356489.3		O95278-1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000766

AC:

AN:

247882

AF XY:

0.0000893

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000993

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000113

AC:

165

AN:

1461590

Hom.:

Cov.:

AF XY:

0.000110

AC XY:

AN XY:

727114

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33474

American (AMR)

AF:

0.000157

AC:

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86230

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53310

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5690

European-Non Finnish (NFE)

AF:

0.000134

AC:

149

AN:

1111984

Other (OTH)

AF:

0.000133

AC:

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41468

American (AMR)

AF:

0.000131

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000118

Hom.:

Bravo

AF:

0.000113

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Lafora disease

Pathogenic:5Other:1

Jan 03, 2025

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

The p.Arg241Ter variant in EPM2A has been reported in many individuals with Lafora disease (PMID: 9771710, 9931343, 11175283, 12019207, 20738377, 21623095, 25246353), segregated with disease in 3 siblings from 1 family (PMID: 25246353), and has been identified In 0.015% (9/59988) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs104893950). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 3098) and has been interpreted as pathogenic by many sources. Of the many affected individuals, at least 2 were homozygotes, which increases the likelihood that the p.Arg241Ter variant is pathogenic (PMID: 9771710). In vitro functional studies provide some evidence that the p.Arg241Ter variant may slightly impact protein function (PMID: 14532330). However, these types of assays may not accurately represent biological function. This nonsense variant leads to a premature termination codon at position 241. This alteration occurs within the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Loss of function of the EPM2A gene is an established disease mechanism in autosomal recessive Lafora disease. The phenotype of individuals compound heterozygous and homozygous for this variant are highly specific for Lafora disease based on biopsies showing Lafora bodies consistent with disease (PMID: 9771710, 11175283, 12019207, 25246353). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Lafora disease. ACMG/AMP Criteria applied: PM3, PVS1_strong, PP4, PS3_supporting, PP1_moderate (Richards 2015). -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 27, 2016

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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. -

Nov 07, 2023

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 05, 2022

DASA

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.721C>T;p.(Arg241*) variant creates a premature translational stop signal in the EPM2A gene. It is expected to result in an absent or disrupted protein product - PVS1_strong. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 3098; PMID: 9771710; PMID: 21623095; PMID: 25246353) - PS4. The variant is present at low allele frequencies population databases (rs104893950 – gnomAD 0.0007161%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. In summary, the currently available evidence indicates that the variant is pathogenic. -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

not provided

Pathogenic:5

Nov 25, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nonsense variant in the C-terminus predicted to result in protein truncation as the last 91 amino acids are lost and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 25525159, 25246353, 20301563, 34755096, 34117373, 9931343, 12019207, 27702709, 28131202, 22047982, 20738377, 21623095, 25481721, 31227012, 31858178, 31758957, 31980526, 33368637, 31589614, 17452581, 9771710, 31476531, 33152654, 34195479, 33773408, 11175283, 24077912) -

Aug 04, 2022

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The EPM2A c.721C>T (p.Arg241Ter) nonsense variant results in the substitution of arginine at amino acid position 241 with a stop codon. This variant occurs in the last exon of the gene and may escape nonsense-mediated mRNA decay. Across a selection of the available literature, the c.721C>T variant, which is described as one of the most common pathogenic EPM2A variants associated with Lafora disease, was identified in a homozygous state in eight unrelated individuals and in a compound heterozygous state in four individuals (PMID: 9771710; PMID: 21623095; PMID: 25246353; PMID: 34755096; PMID: 33773408). Additionally, this variant was also reported in 12 affected individuals, phase unknown (PMID: 11175283). The c.721C>T variant segregated with disease in one family (PMID: 25246353). The highest frequency of this allele in the Genome Aggregation Database is 0.000198 in the Latino/Admixed American population (version 2.1.1. Based on the available evidence, the c.721C>T (p.Arg241Ter) variant is classified as pathogenic for Lafora disease. -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Pathogenic:1

Jun 22, 2018

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R241* pathogenic mutation (also known as c.721C>T), located in coding exon 4 of the EPM2A gene, results from a C to T substitution at nucleotide position 721. This changes the amino acid from an arginine to a stop codon within coding exon 4. This mutation is a well described Spanish founder mutation and accounts for up to 40% of pathogenic alleles in Lafora disease. It has been detected numerous times both in the homozygous and compound heterozygous states in Lafora disease cohorts (Minassian BA et al. Nat. Genet., 1998 Oct;20:171-4; Harirchian MH et al. Indian J Pathol Microbiol;54:374-5; Jara-Prado A et al. Epilepsy Res., 2014 Nov;108:1501-10; Gómez-Garre P et al. Eur. J. Hum. Genet., 2000 Dec;8:946-54; Lesca G et al. Epilepsia, 2010 Sep;51:1691-8). In addition, in one in vitro study, this mutation showed loss of phosphatase enzyme activity and also lacked the capacity to bind to glycogen (Fernández-Sánchez ME et al. Hum. Mol. Genet., 2003 Dec;12:3161-71). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

EPM2A-related disorder

Pathogenic:1

Sep 09, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The EPM2A c.721C>T variant is predicted to result in premature protein termination (p.Arg241*). This variant was reported in patients with progressive myoclonus epilepsy (Jara-Prado et al. 2014. PubMed ID: 25246353; El Tahry et al. 2015. PubMed ID: 25481721). This variant is reported in 0.020% of alleles in individuals of Latino descent in gnomAD. Nonsense variants in EPM2A are expected to be pathogenic. This variant is interpreted as pathogenic. -

Progressive myoclonic epilepsy

Pathogenic:1

Aug 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Arg241*) in the EPM2A gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 91 amino acid(s) of the EPM2A protein. This variant is present in population databases (rs104893950, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with Lafora 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. -

Myoclonic epilepsy of Lafora 1

Pathogenic:1

Dec 01, 2000

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.63

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.49

T;T

MetaRNN

Pathogenic

0.80

D;D

PhyloP100

5.7

GERP RS

4.8

Mutation Taster

=4/196

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over