Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV001266215 | SCV001444387 | likely pathogenic | Inborn genetic diseases | 2019-04-18 | criteria provided, single submitter | clinical testing | |
Invitae | RCV001381016 | SCV001579267 | pathogenic | Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11 | 2020-06-06 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This missense change has been observed in individual(s) with epilepsy (PMID: 30415926, 26291284, 23708187). In at least one individual the variant was observed to be de novo. This sequence change replaces methionine with isoleucine at codon 136 of the SCN2A protein (p.Met136Ile). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and isoleucine. |
Mayo Clinic Laboratories, |
RCV001507573 | SCV001713195 | pathogenic | not provided | 2020-06-17 | criteria provided, single submitter | clinical testing | PS1, PS2, PM2, PP2 |
Rady Children's Institute for Genomic Medicine, |
RCV003985489 | SCV001984847 | pathogenic | SCN2A-related disorder | 2020-06-16 | criteria provided, single submitter | clinical testing | This variant has been previously reported as a de novo heterozygous change in an individual with refractory seizures and severe axial hypotonia (PMID: 30415926). In addition, a different de novo heterozygous variant at the same nucleotide resulting in the same amino acid change, c.408G>T (p.Met136Ile), has been previously reported in an individual with early onset epileptic encephalopathy evolving to infantile spasms (PMID: 23708187). It is absent from the gnomAD population database and thus is presumed to be rare. The c.408G>A (p.Met136Ile) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.408G>A (p.Met136Ile) variant is classified as Pathogenic. |