chr6-145627667-C-A
Variant summary
Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM2PP3PP5
The NM_005670.4(EPM2A):c.745G>T(p.Val249Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,812 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V249M) has been classified as Uncertain significance.
Frequency
Consequence
NM_005670.4 missense
Scores
Clinical Significance
Conservation
Publications
- Lafora diseaseInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, PanelApp Australia
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ACMG classification
Our verdict: Likely_pathogenic. The variant received 6 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461812Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727206 show subpopulations
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Lafora disease Pathogenic:1
The p.Val249Leu variant in EPM2A has been reported, in the compound heterozygous state, in 1 individual with Lafora disease (PMID: 33277415), and has been identified in 0.00009% (1/1111976) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1387516050). 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: 462933) and has been interpreted as pathogenic by Invitae and a variant of uncertain significance by GeneDx. In vitro functional studies provide some evidence that the p.Val249Leu variant may slightly impact protein function (Donahue et al. 2023). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The phenotype of an individual compound heterozygous for this variant was highly specific for Lafora disease based on a biopsy showing Lafora bodies consistent with disease (PMID: 33277415). 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, PP4_moderate, PM2_supporting, PS3_supporting (Richards 2015). -
Progressive myoclonic epilepsy Pathogenic:1
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 sequence change replaces valine with leucine at codon 249 of the EPM2A protein (p.Val249Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of Lafora disease (Invitae). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. -
not provided Uncertain:1
Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 33277415) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at