Submissions for variant NM_005670.4(EPM2A):c.136G>A (p.Ala46Thr)

dbSNP: rs374338349

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000187406	SCV000240993	uncertain significance	not provided	2024-05-19	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis indicates that this missense variant does not alter protein structure/function
Labcorp Genetics (formerly Invitae), Labcorp	RCV000528451	SCV000636471	uncertain significance	Progressive myoclonic epilepsy	2022-09-07	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 46 of the EPM2A protein (p.Ala46Thr). This variant is present in population databases (no rsID available, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with EPM2A-related conditions. ClinVar contains an entry for this variant (Variation ID: 205444). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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.
Fulgent Genetics, Fulgent Genetics	RCV000765870	SCV000897267	uncertain significance	Lafora disease	2018-10-31	criteria provided, single submitter	clinical testing
New York Genome Center	RCV001263351	SCV001441393	uncertain significance	Seizure	2020-02-06	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002381628	SCV002700322	uncertain significance	Inborn genetic diseases	2018-07-31	criteria provided, single submitter	clinical testing	The p.A46T variant (also known as c.136G>A), located in coding exon 1 of the EPM2A gene, results from a G to A substitution at nucleotide position 136. The alanine at codon 46 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV003927738	SCV004744947	likely benign	EPM2A-related disorder	2022-03-18	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).