Submissions for variant NM_018100.4(EFHC1):c.810T>G (p.Asp270Glu)

dbSNP: rs796052413

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000187347	SCV000240932	uncertain significance	not provided	2012-11-08	criteria provided, single submitter	clinical testing	The Asp270Glu missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI ESP Exome Variant Project has not identified Asp270Glu in approximately 6,500 individuals of European or African American ethnicity, indicating that it is not a common benign variant in these populations. Asp270Glu alters a highly conserved position in the second DM10 domain of the EFHC1 protein, and other missense mutations in this domain have been reported in association with epilepsy. Additionally, multiple in silico algorithms predict Asp270Glu may be damaging to the structure/function of the protein. However, the amino acid substitution is conservative as both Glutamic acid and Aspartic acid are negatively charged, polar amino acid residues. The presence of Asp270Glu in this unaffected parent does not alter the interpretation ofthis variant, as some individuals with EFHC1 mutations do not develop seizures or epileptiform EEG discharges due to incomplete penetrance (Suzuki et al., 2005; Medina et al., 2008). The variant is found in EPILEPSY panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV003765175	SCV002180346	uncertain significance	Absence seizure; Myoclonic epilepsy, juvenile, susceptibility to, 1	2021-08-16	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid with glutamic acid at codon 270 of the EFHC1 protein (p.Asp270Glu). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with EFHC1-related conditions. ClinVar contains an entry for this variant (Variation ID: 205390). 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. 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.