ClinVar Miner

Submissions for variant NM_002180.2(IGHMBP2):c.1148C>T (p.Ala383Val) (rs876661217)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000220132 SCV000279814 uncertain significance not provided 2016-01-20 criteria provided, single submitter clinical testing The c.1148 C>T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant 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. Multiple in-silico splice prediction models predict that c.1148 C>T may create a cryptic splice donor site in exon 8 which may supplant the natural donor site and lead to abnormal splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. If c.1148 C>T does not alter splicing, it will result in the A383V missense substitution, which 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 conserved in mammals, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, missense variants in nearby residues (V373G, E382K, W386R) 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 this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000642614 SCV000764301 uncertain significance Spinal muscular atrophy, distal, autosomal recessive, 1; Charcot-Marie-Tooth disease, axonal, type 2S 2018-11-09 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 383 of the IGHMBP2 protein (p.Ala383Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with IGHMBP2-related disease. ClinVar contains an entry for this variant (Variation ID: 234786). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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