ClinVar Miner

Submissions for variant NM_002180.2(IGHMBP2):c.1766G>T (p.Gly589Val) (rs764900781)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000520882 SCV000618839 uncertain significance not provided 2017-07-07 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the IGHMBP2 gene. The G589V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The G589V variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G589V 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 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. Of note, an external source has observed individuals apparently homozygous (by WES) for this variant with spinal muscular atrophy with respiratory failure; however, additional evidence is not currently available to GeneDx.
Invitae RCV000642626 SCV000764313 uncertain significance Spinal muscular atrophy, distal, autosomal recessive, 1; Charcot-Marie-Tooth disease, axonal, type 2S 2018-05-31 criteria provided, single submitter clinical testing This sequence change replaces glycine with valine at codon 589 of the IGHMBP2 protein (p.Gly589Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. This variant is present in population databases (rs764900781, ExAC 0.02%). This variant has not been reported in the literature in individuals with IGHMBP2-related disease. ClinVar contains an entry for this variant (Variation ID: 450280). 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: "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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