rs104893950

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_005670.4(EPM2A):c.721C>T(p.Arg241Ter) 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 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:13O:1

Conservation

PhyloP100: 5.66

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 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 7 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 6-145627691-G-A is Pathogenic according to our data. Variant chr6-145627691-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 3098.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-145627691-G-A is described in Lovd as [Pathogenic]. Variant chr6-145627691-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPM2A	NM_005670.4 linkuse as main transcript	c.721C>T	p.Arg241Ter	stop_gained, splice_region_variant	4/4	ENST00000367519.9	NP_005661.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPM2A	ENST00000367519.9 linkuse as main transcript	c.721C>T	p.Arg241Ter	stop_gained, splice_region_variant	4/4	1	NM_005670.4	ENSP00000356489	P1	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

GnomAD3 exomes

AF:

0.0000766

AC:

AN:

247882

Hom.:

AF XY:

0.0000893

AC XY:

AN XY:

134422

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 SAS 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

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000134

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000155

Hom.:

Bravo

AF:

0.000113

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 04, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 25, 2022	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) -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Lafora disease

Pathogenic:4Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Jun 27, 2016	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 07, 2023	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Mar 05, 2022	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. -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 22, 2018

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

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 09, 2024

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 01, 2023

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2000

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.63

CADD

Pathogenic

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

MutationTaster

Benign

1.0

GERP RS

4.8

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over