rs104893950

chr6-145627691-G-Achr6-145627691-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12 O:1
• Conservation: PhyloP100: 5.66

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 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 22 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	UniProt
EPM2A	NM_005670.4	c.721C>T	p.Arg241Ter	stop_gained, splice_region_variant	4/4	ENST00000367519.9

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152232 Hom.: 0 Cov.: 33

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: 19 AN: 247882 Hom.: 0 AF XY: 0.0000893 AC XY: 12 AN XY: 134422

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.: 0 Cov.: 32 AF XY: 0.000110 AC XY: 80 AN XY: 727114

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: 9 AN: 152232 Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5 AN XY: 74382

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.: 0

Bravo AF: 0.000113

ExAC AF: 0.0000741 AC: 9

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lafora disease Pathogenic:5 Other:1

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. -
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. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2000	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 07, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

not provided Pathogenic:5

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

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. -

Progressive myoclonic epilepsy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.63
Cadd	Pathogenic	45
Dann	Uncertain	1.0
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.49	T;T
MetaRNN	Pathogenic	0.80	D;D
MutationTaster	Benign	1.0	A
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

Other links and lift over

dbSNP: rs104893950; hg19: chr6-145948827; COSMIC: COSV62296130;