Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000187338 | SCV000240922 | uncertain significance | not provided | 2014-07-07 | criteria provided, single submitter | clinical testing | p.Tyr115Cys (TAT>TGT): c.344 A>G in exon 3 of the EFHC1 gene (NM_018100.3). The Y115C variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position that is conserved in mammals, but is not conserved in more distantly related species and Cysteine has been seen at this position in one species in evolution. However, a missense mutation in a nearby residue (R118C) has been reported in association with juvenile myoclonic epilepsy. Additionally, the Y115C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in EPILEPSY panel(s). |
| Invitae | RCV003765169 | SCV000931699 | uncertain significance | Absence seizure; Myoclonic epilepsy, juvenile, susceptibility to, 1 | 2022-11-22 | criteria provided, single submitter | clinical testing | 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. 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) performed at Invitae indicates that this missense variant is not expected to disrupt EFHC1 protein function. ClinVar contains an entry for this variant (Variation ID: 205381). This variant has not been reported in the literature in individuals affected with EFHC1-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 115 of the EFHC1 protein (p.Tyr115Cys). |