Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000235714 | SCV000294155 | uncertain significance | not provided | 2016-05-11 | criteria provided, single submitter | clinical testing | The R254H variant has has not been published as a pathogenic variant, nor has it been reported as a benign variant 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. The R254H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and missense variants in nearby residues (L251P; A256G) have been reported in the Human Gene Mutation Database in association with IGHMBP2-related disorders (Stenson et al., 2014). Additionally, in silico analysis predicts this variant is probably 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. |
Invitae | RCV000696905 | SCV000825486 | uncertain significance | Spinal muscular atrophy, distal, autosomal recessive, 1; Charcot-Marie-Tooth disease, axonal, type 2S | 2018-03-29 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine with histidine at codon 254 of the IGHMBP2 protein (p.Arg254His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs761191746, ExAC 0.001%). This variant has not been reported in the literature in individuals with IGHMBP2-related disease. ClinVar contains an entry for this variant (Variation ID: 246563). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. |
Genomic Research Center, |
RCV000790913 | SCV000930160 | uncertain significance | not specified | 2019-04-27 | criteria provided, single submitter | clinical testing |