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

gnomAD frequency: 0.00015  dbSNP: rs141919651

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000187386	SCV000240973	uncertain significance	not provided	2024-09-10	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	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
Ambry Genetics	RCV004619219	SCV005119050	uncertain significance	Inborn genetic diseases	2024-05-15	criteria provided, single submitter	clinical testing	The c.488A>G (p.N163S) alteration is located in exon 3 (coding exon 3) of the EPM2A gene. This alteration results from a A to G substitution at nucleotide position 488, causing the asparagine (N) at amino acid position 163 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
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.