ClinVar Miner

Submissions for variant NM_002180.2(IGHMBP2):c.856C>T (p.Arg286Trp) (rs751421003)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236339 SCV000293131 uncertain significance not provided 2015-09-11 criteria provided, single submitter clinical testing The R286W variant has not been published as a pathogenic, 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. The R286W 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. Additionally, this substitution occurs at a position that is conserved in mammals, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with IGHMBP2-related disorders (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000802136 SCV000941954 uncertain significance Spinal muscular atrophy, distal, autosomal recessive, 1; Charcot-Marie-Tooth disease, axonal, type 2S 2018-10-31 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 286 of the IGHMBP2 protein (p.Arg286Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs751421003, ExAC 0.009%). This variant has not been reported in the literature in individuals with IGHMBP2-related disease. ClinVar contains an entry for this variant (Variation ID: 245927). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably 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.

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