rs587776553

Variant names:

• chr6-145686262-G-GT
• rs587776553
• NM_005670.4:c.335dupA

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_005670.4(EPM2A):​c.335dupA​(p.Tyr112fs) variant causes a frameshift, stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,660 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: EPM2A NM_005670.4 frameshift, stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.36

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 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-145686262-G-GT is Pathogenic according to our data. Variant chr6-145686262-G-GT is described in ClinVar as [Pathogenic]. Clinvar id is 3101.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPM2A	NM_005670.4	c.335dupA	p.Tyr112fs	frameshift_variant, stop_gained	Exon 2 of 4	ENST00000367519.9	NP_005661.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPM2A	ENST00000367519.9	c.335dupA	p.Tyr112fs	frameshift_variant, stop_gained	Exon 2 of 4	1	NM_005670.4	ENSP00000356489.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461660 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727154

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Lafora disease Pathogenic:1

Jan 06, 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.Tyr112Ter (c.335dup) variant in EPM2A has been reported in 2 individuals with Lafora disease (PMID: 9931343, 30041081), and has been identified in 0.001% (1/86250) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs587776553). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 3101) and has been interpreted as pathogenic by OMIM. Of the 2 affected individuals, 1 of those was a homozygote, which increases the likelihood that the p.Tyr112Ter variant is pathogenic (PMID: 9931343). In vitro functional studies provide some evidence that the p.Tyr112Ter variant may impact protein function (PMID: 30041081). However, these types of assays may not accurately represent biological function. This nonsense variant leads to a premature termination codon at position 112, which is predicted to lead to a truncated or absent protein. Loss of function of the EPM2A gene is an established disease mechanism in autosomal recessive Lafora disease. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Lafora disease. ACMG/AMP Criteria applied: PVS1, PM2_supporting, PM3_supporting, PS3_moderate (Richards 2015). -

Myoclonic epilepsy of Lafora 1 Pathogenic:1

Oct 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs587776553; hg19: chr6-146007398;