Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000544537 | SCV000657951 | uncertain significance | Charcot-Marie-Tooth disease type 4 | 2019-12-31 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine with valine at codon 1055 of the SBF2 protein (p.Ile1055Val). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs142891020, ExAC 0.004%) but has not been reported in the literature in individuals with an SBF2-related disease. 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, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. |
| ARUP Laboratories, |
RCV000757736 | SCV000886074 | uncertain significance | not provided | 2017-11-09 | criteria provided, single submitter | clinical testing | The p.Ile1055Val variant (rs142891020) has not been reported in the medical literature, and it is not listed in gene-specific variant databases. The p.Ile1055Val variant is listed in the Genome Aggregation Database (gnomAD) browser with an overall allele frequency of 0.002% (identified in 5 out of 246,176 chromosomes). The isoleucine at codon 1055 is moderately conserved considering 11 species (Alamut software v2.10.0), and computational analyses predict conflicting effects of this variant on protein structure/function (SIFT: tolerated, PolyPhen2: benign, MutationTaster: disease causing). Based on the available information, the clinical significance of the p.Ile1055Val variant cannot be determined with certainty. |
| Illumina Clinical Services Laboratory, |
RCV001114471 | SCV001272358 | uncertain significance | Charcot-Marie-Tooth disease, type 4B2 | 2018-01-12 | criteria provided, single submitter | clinical testing | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. |