rs137852917

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_ModeratePP5_Moderate

The NM_005670.4(EPM2A):c.835G>T(p.Gly279Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

EPM2A
NM_005670.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 7.57

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1

In a domain Tyrosine-protein phosphatase (size 167) in uniprot entity EPM2A_HUMAN there are 10 pathogenic changes around while only 1 benign (91%) in NM_005670.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.936

PP5

Variant 6-145627577-C-A is Pathogenic according to our data. Variant chr6-145627577-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 834981.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPM2A	NM_005670.4 link	c.835G>T	p.Gly279Cys	missense_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.835G>T	p.Gly279Cys	missense_variant	Exon 4 of 4	1	NM_005670.4	ENSP00000356489.3		O95278-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000800

AC:

AN:

249864

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135196

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Lafora disease

Pathogenic:1

Jan 03, 2025

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Gly279Cys variant in EPM2A has been reported in 5 individuals with Lafora disease (PMID: 25246353, 34755096), segregated with disease in four affected relatives from one family (PMID: 25246353), and has been identified in in 0.004% (2/44724) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs137852917). 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: 834981) and has been interpreted as pathogenic by Invitae. Of the 5 affected individuals, at least 1 was a compound heterozygote that carried a reported pathogenic variant in trans, which increases the likelihood that the p.Gly279Cys variant is pathogenic (Variation ID: 3098; PMID: 25246353). In vitro functional studies provide some evidence that the p.Gly279Cys variant may impact protein function (PMID: 34755096). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional likely pathogenic variant, resulting in a different amino acid change at the same position, p.Gly279Ser, has been reported in association with disease in ClinVar, slightly supporting that a change at this position may not be tolerated (Variation ID: 2099). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive Lafora disease. ACMG/AMP Criteria applied: PM3, PP1_moderate, PP3_moderate, PM2_supporting, PS3_supporting, PM5_supporting (Richards 2015). -

Progressive myoclonic epilepsy

Pathogenic:1

Nov 18, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed to segregate with late-onset Lafora disease in a family (PMID: 25246353). This variant is present in population databases (rs137852917, ExAC 0.02%). This sequence change replaces glycine with cysteine at codon 279 of the EPM2A protein (p.Gly279Cys). The glycine residue is highly conserved and there is a large physicochemical difference between glycine and cysteine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.62

D;.;.;.;.;.;.;.

Eigen

Uncertain

0.63

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

D;.;D;.;.;.;.;D

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.94

D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.86

MutationAssessor

Benign

1.1

L;.;L;.;L;.;.;.

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-4.3

D;.;.;.;.;.;.;.

REVEL

Pathogenic

0.80

Sift

Uncertain

0.023

D;.;.;.;.;.;.;.

Sift4G

Uncertain

0.010

D;.;D;D;.;.;.;.

Polyphen

1.0

D;.;D;.;D;.;.;.

Vest4

0.82

MutPred

0.80

Loss of MoRF binding (P = 0.0754);.;Loss of MoRF binding (P = 0.0754);.;Loss of MoRF binding (P = 0.0754);.;.;.;

MVP

0.87

MPC

0.90

ClinPred

0.98

GERP RS

5.7

gMVP

0.82

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