NM_005670.4(EPM2A):c.94T>A (p.Trp32Arg) AND Progressive myoclonic epilepsy

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Apr 5, 2018
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:: RCV000686981.7

Allele description [Variation Report for NM_005670.4(EPM2A):c.94T>A (p.Trp32Arg)]

NM_005670.4(EPM2A):c.94T>A (p.Trp32Arg)

Genes:

LOC129997381:ATAC-STARR-seq lymphoblastoid silent region 17642 [Gene]
EPM2A-DT:EPM2A divergent transcript [Gene - HGNC]
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.94T>A (p.Trp32Arg)

HGVS:

NC_000006.12:g.145735405A>T
NG_012832.2:g.5451T>A
NM_001018041.2:c.94T>A
NM_001360057.2:c.94T>A
NM_001360064.2:c.-114+503T>A
NM_001360071.2:c.-576T>A
NM_001368129.2:c.-530T>A
NM_001368130.1:c.94T>A
NM_001368131.1:c.-274T>A
NM_005670.4:c.94T>AMANE SELECT
NP_001018051.1:p.Trp32Arg
NP_001346986.1:p.Trp32Arg
NP_001355059.1:p.Trp32Arg
NP_005661.1:p.Trp32Arg
NC_000006.11:g.146056541A>T
NG_012832.1:g.5451T>A
NM_005670.3:c.94T>A

Protein change:

W32R

Links:

dbSNP: rs104893955

NCBI 1000 Genomes Browser:

rs104893955

Molecular consequence:

NM_001360071.2:c.-576T>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001368129.2:c.-530T>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001368131.1:c.-274T>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001360064.2:c.-114+503T>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001018041.2:c.94T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001360057.2:c.94T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001368130.1:c.94T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_005670.4:c.94T>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000814527	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Apr 5, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000814527

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Apr 5, 2018)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000814527.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This sequence change replaces tryptophan with arginine at codon 32 of the EPM2A protein (p.Trp32Arg). The tryptophan residue is moderately conserved and there is a moderate physicochemical difference between tryptophan and arginine. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). A different missense substitution at this codon (p.Trp32Gly) has been determined to be pathogenic (PMID:¬†10932264,¬†11739371,¬†12019207,¬†14532330). This suggests that the tryptophan residue is critical for EPM2A protein function and that other missense substitutions at this position may also be pathogenic. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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