Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000171042 | SCV000223606 | uncertain significance | not provided | 2015-09-16 | criteria provided, single submitter | clinical testing | p.Val123Ile (GTC>ATC): c.367 G>A in exon 3 of the SCN1B gene (NM_001037.4). The V123I missense change 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. V123I alters a conserved position in the SCN1B protein and another missense mutation in this region of the protein has been reported in association with generalized epilepsy with febrile seizures plus (GEFS+) (Wallace et al., 1998). However, the V123I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, and 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 V123I is a disease-causing mutation or a rare benign variant. The variant is found in CHILD-EPI,EPILEPSY panel(s). |
| Invitae | RCV001315548 | SCV001506126 | uncertain significance | Brugada syndrome 5 | 2022-07-19 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 123 of the SCN1B protein (p.Val123Ile). 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 variant has not been reported in the literature in individuals affected with SCN1B-related conditions. ClinVar contains an entry for this variant (Variation ID: 190862). 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 tolerated. 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. |
| Ambry Genetics | RCV002453586 | SCV002615259 | likely benign | Cardiovascular phenotype | 2019-07-04 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. |