Submissions for variant NM_005670.4(EPM2A):c.488A>G (p.Asn163Ser)

gnomAD frequency: 0.00015  dbSNP: rs141919651

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000187386	SCV000240973	uncertain significance	not provided	2017-12-20	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the EPM2A gene. The N163S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The N163S variant is observed in 41/126670 (0.03%) alleles from individuals of European background in large population cohorts (Lek et al., 2016). The N163S variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. In addition, a different missense change at this residue (N163D) has been reported as pathogenic at GeneDx in association with epilepsy. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV000696786	SCV000825365	uncertain significance	Progressive myoclonic epilepsy	2023-08-17	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 163 of the EPM2A protein (p.Asn163Ser). This variant is present in population databases (rs141919651, gnomAD 0.03%). 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: 205426). 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. 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	RCV000765868	SCV000897265	uncertain significance	Lafora disease	2018-10-31	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000187386	SCV001551227	uncertain significance	not provided		no assertion criteria provided	clinical testing	The EPM2A p.Asn163Ser variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs141919651) and in ClinVar (classified as a VUS by GeneDx in 2017, Invitae in 2018, and Fulgent in 2018). The variant was identified in control databases in 46 of 282834 chromosomes at a frequency of 0.000163 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 43 of 129146 chromosomes (freq: 0.000333), European (Finnish) in 2 of 25122 chromosomes (freq: 0.00008) and South Asian in 1 of 30616 chromosomes (freq: 0.000033); it was not observed in the African, Latino, Ashkenazi Jewish, East Asian, and Other populations. Another missense change at this residue (N163D) has been reported as likely pathogenic by GeneDx in association with epilepsy. The variant is located with the Dual specificity phosphatase, subgroup, catalytic domain functional domain(s) of the laforin protein, increasing the likelihood that it may have clinical significance. The p.Asn163 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (MaxEntScan) do not predict a greater than 10% difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.