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NM_005670.4(EPM2A):c.512G>A (p.Arg171His) AND Progressive myoclonic epilepsy

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Dec 22, 2023
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000469417.8

Allele description [Variation Report for NM_005670.4(EPM2A):c.512G>A (p.Arg171His)]

NM_005670.4(EPM2A):c.512G>A (p.Arg171His)

Gene:
EPM2A:EPM2A glucan phosphatase, laforin [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
6q24.3
Genomic location:
Preferred name:
NM_005670.4(EPM2A):c.512G>A (p.Arg171His)
HGVS:
  • NC_000006.12:g.145635451C>T
  • NG_012832.2:g.105405G>A
  • NM_001018041.2:c.512G>A
  • NM_001360057.2:c.477-7758G>A
  • NM_001360064.2:c.98G>A
  • NM_001360071.2:c.98G>A
  • NM_001368129.2:c.50G>A
  • NM_001368130.1:c.512G>A
  • NM_001368131.1:c.98G>A
  • NM_001368132.1:c.50G>A
  • NM_005670.4:c.512G>AMANE SELECT
  • NP_001018051.1:p.Arg171His
  • NP_001346993.1:p.Arg33His
  • NP_001347000.1:p.Arg33His
  • NP_001355058.1:p.Arg17His
  • NP_001355059.1:p.Arg171His
  • NP_001355060.1:p.Arg33His
  • NP_001355061.1:p.Arg17His
  • NP_005661.1:p.Arg171His
  • NC_000006.11:g.145956587C>T
  • NG_012832.1:g.105405G>A
  • NM_005670.3:c.512G>A
  • O95278:p.Arg171His
Protein change:
R171H; ARG171HIS
Links:
UniProtKB: O95278#VAR_019474; OMIM: 607566.0005; dbSNP: rs137852916
NCBI 1000 Genomes Browser:
rs137852916
Molecular consequence:
  • NM_001360057.2:c.477-7758G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001018041.2:c.512G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001360064.2:c.98G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001360071.2:c.98G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001368129.2:c.50G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001368130.1:c.512G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001368131.1:c.98G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001368132.1:c.50G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_005670.4:c.512G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Progressive myoclonic epilepsy
Synonyms:
Myoclonic Epilepsies, Progressive; Familial progressive myoclonic epilepsy; Progressive myoclonus epilepsy; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0020074; MedGen: C0751778; Orphanet: 308; OMIM: PS254800

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000552393Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Likely pathogenic
(Dec 22, 2023) 		germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

A novel protein tyrosine phosphatase gene is mutated in progressive myoclonus epilepsy of the Lafora type (EPM2).

Serratosa JM, Gómez-Garre P, Gallardo ME, Anta B, de Bernabé DB, Lindhout D, Augustijn PB, Tassinari CA, Malafosse RM, Topcu M, Grid D, Dravet C, Berkovic SF, de Córdoba SR.

Hum Mol Genet. 1999 Feb;8(2):345-52.

PubMed [citation]
PMID:
9931343

Mutation spectrum and predicted function of laforin in Lafora's progressive myoclonus epilepsy.

Minassian BA, Ianzano L, Meloche M, Andermann E, Rouleau GA, Delgado-Escueta AV, Scherer SW.

Neurology. 2000 Aug 8;55(3):341-6.

PubMed [citation]
PMID:
10932264
See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000552393.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 171 of the EPM2A protein (p.Arg171His). This variant is present in population databases (rs137852916, gnomAD 0.004%). This missense change has been observed in individual(s) with Lafora disease (PMID: 9931343, 10932264, 12019207, 34568804). ClinVar contains an entry for this variant (Variation ID: 3102). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on EPM2A protein function. Experimental studies have shown that this missense change affects EPM2A function (PMID: 25544560). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024