ClinVar Miner

Submissions for variant NM_002180.2(IGHMBP2):c.736A>G (p.Ile246Val) (rs377678376)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236419 SCV000293137 uncertain significance not provided 2015-09-04 criteria provided, single submitter clinical testing The I246V variant has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. It was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The I246V 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 where amino acids with similar properties to Isoleucine are tolerated across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Additionally, missense mutations in nearby residues (C241R; N245S; L251P) have been reported in the Human Gene Mutation Database in association with IGHMBP2-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, based on the currently available information, it is unclear whether the I246V variant is a pathogenic variant or a rare benign variant.
Invitae RCV001246118 SCV001419456 uncertain significance Spinal muscular atrophy, distal, autosomal recessive, 1; Charcot-Marie-Tooth disease, axonal, type 2S 2019-11-05 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 246 of the IGHMBP2 protein (p.Ile246Val). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs377678376, ExAC 0.003%). This variant has not been reported in the literature in individuals with IGHMBP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 245931). 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 valine 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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