Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000189131 | SCV000242763 | uncertain significance | not provided | 2015-05-12 | criteria provided, single submitter | clinical testing | The Asp1064Tyr 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 Asp1064Tyr in approximately 6,500 individuals of European or African American ethnicity, indicating that it is not a common benign variant in these populations. The amino acid substitution is non-conservative as a negatively charged Aspartic acid residue is replaced by an uncharged Tyrosine residue. In addition, Asp1064Tyr alters a position that is conserved in mammals, and is within the intracellular loop between the second and third transmembrane domain of the SCN2A protein where other missense mutations have been published in association with neonatal-infantile seizures (Berkovic et al., 2004; Ogiwara et al., 2009). However, in-silico algorithms are not consistent in their predictions as to whether Asp1064Tyr is damaging to the structure/function of the protein. Therefore, based on the currently available information, it is unclear whether Asp1064Tyr is a disease-causing mutation or a rare benign variant. The variant is found in CHILD-EPI panel(s). |
Invitae | RCV000228684 | SCV000290577 | uncertain significance | Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11 | 2023-12-23 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 1064 of the SCN2A protein (p.Asp1064Tyr). This variant is present in population databases (rs769395683, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with SCN2A-related conditions. ClinVar contains an entry for this variant (Variation ID: 206982). 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 expected to disrupt SCN2A protein function with a positive predictive value of 95%. 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, |
RCV000228684 | SCV000895297 | uncertain significance | Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11 | 2018-10-31 | criteria provided, single submitter | clinical testing |