ClinVar Miner

Submissions for variant NM_002180.2(IGHMBP2):c.830A>G (p.Gln277Arg) (rs112495985)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000442407 SCV000534416 uncertain significance not provided 2016-12-02 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the IGHMBP2 gene. The Q277R variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The Q277R 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 Q277R variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Additionally, this substitution is predicted to be within the helicase domain (Lim et al., 2012; Cottenie et al., 2014; Jedrzejowska et al., 2014). 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.
Invitae RCV000703580 SCV000832486 uncertain significance Spinal muscular atrophy, distal, autosomal recessive, 1; Charcot-Marie-Tooth disease, axonal, type 2S 2018-10-11 criteria provided, single submitter clinical testing This sequence change replaces glutamine with arginine at codon 277 of the IGHMBP2 protein (p.Gln277Arg). The glutamine residue is weakly conserved and there is a small physicochemical difference between glutamine and arginine. This variant is present in population databases (rs112495985, ExAC 0.03%). This variant has not been reported in the literature in individuals with IGHMBP2-related disease. ClinVar contains an entry for this variant (Variation ID: 391360). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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