Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000229019 | SCV000291891 | uncertain significance | Brugada syndrome 5 | 2024-01-26 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 225 of the SCN1B protein (p.Arg225Cys). This variant is present in population databases (rs369588692, gnomAD 0.02%). This missense change has been observed in individual(s) with sudden infant death syndrome (PMID: 28074886, 29915715). ClinVar contains an entry for this variant (Variation ID: 242250). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects SCN1B function (PMID: 29915715). 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. |
Gene |
RCV000489204 | SCV000577143 | uncertain significance | not specified | 2017-04-10 | criteria provided, single submitter | clinical testing | A variant of uncertain significance has been identified in an alternative transcript of the SCN1B gene. The R225C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R225C variant is observed in 2/8002 (0.02%) alleles from individuals of South Asian background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R225C 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. However, this substitution occurs at a position that is not conserved. 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 variant or a rare benign variant. |