ClinVar Miner

Submissions for variant NM_002180.2(IGHMBP2):c.1844G>A (p.Arg615His) (rs201640213)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235293 SCV000293058 uncertain significance not provided 2018-06-20 criteria provided, single submitter clinical testing The R615H variant has not been published as pathogenic, nor has it been reported as a benign polymorphism to our knowledge. The R615H variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project or in the 1000 Genomes Project. The R615H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved, and Histidine is observed at this position in evolution. However, missense variants in nearby residues (A609E, R606H) have been reported in the Human Gene Mutation Database in association with spinal muscular atrophy with respiratory distress (Stenson et al., 2014). 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 RCV000551552 SCV000642327 uncertain significance Spinal muscular atrophy, distal, autosomal recessive, 1; Charcot-Marie-Tooth disease, axonal, type 2S 2018-12-14 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 615 of the IGHMBP2 protein (p.Arg615His). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs201640213, ExAC 0.03%). This variant has not been reported in the literature in individuals with an IGHMBP2-related disease. ClinVar contains an entry for this variant (Variation ID: 245883). 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 histidine 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, this variant has uncertain impact on IGHMBP2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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