Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000521033 | SCV000619131 | pathogenic | not provided | 2022-04-11 | criteria provided, single submitter | clinical testing | Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 124 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Lost region is predicted to be within the C-terminal cytoplasmic domain and contains the IQ domain; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge |
| Ambry Genetics | RCV002350149 | SCV002651769 | likely pathogenic | Inborn genetic diseases | 2017-06-19 | criteria provided, single submitter | clinical testing | The p.R1882* variant (also known as c.5644C>T), located in coding exon 26 of the SCN2A gene, results from a C to T substitution at nucleotide position 5644. This changes the amino acid from an arginine to a stop codon within coding exon 26. Premature stop codons are typically deleterious in nature, however, this stop codon occurs at the 3' terminus of SCN2A, and is not expected to trigger nonsense-mediated mRNA decay. This alteration is expected to result in loss of function by premature protein truncation. This alteration removes the last 124 amino acids of the protein, but the exact functional impact of these removed amino acids is unknown at this time. This variant is indicated to be structurally destabilizing (Ambry internal data; Wu J et al. Science, 2015 Dec;350:aad2395; Guo J et al. Nature, 2016 Mar;531:196-201; Guo J et al. Proc. Natl. Acad. Sci. U.S.A., 2017 Jan;114:1009-1014; Shen H et al. Science, 2017 Mar;355). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Victorian Clinical Genetics Services, |
RCV002470897 | SCV002768485 | pathogenic | Developmental and epileptic encephalopathy, 11 | 2022-02-02 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with SCN2A-related disorders. Variants causing a gain of function result in either developmental and epileptic encephalopathy 11 (MIM#613721) or benign familial infantile seizures 3 (MIM#607745), whereas variants displaying a loss of function cause austism spectrum disorder and/or intellectual disability, with or without childhood-onset seizures (OMIM, PMID: 29691040). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0601 - Variant results in the truncation of the well-established C-terminal IQ motif. Functional studies on this motif demonstrated that this region is essential for regulating calmodulin binding, and calcium ion binding affinity (PMID: 21439835). Additionally, HEK293 cells transfected with truncated protein displayed reductions in current density, channel availability, protein expression and a hyperpolarizing shift in voltage (PMID: 34156984). (SP) 0708 - Other protein truncating variants comparable to the one identified in this case have conflicting previous evidence for pathogenicity. These variants (p.(Gln1913*) and p.(Ser1958*)) have been reported as likely pathogenic and VUS, respectively (ClinVar). (I) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. This variant has been reported once as pathogenic (ClinVar). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1102 - Strong phenotype match for this individual. (SP) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |