Submissions for variant NM_002180.2(IGHMBP2):c.1295C>T (p.Ala432Val) (rs370414354)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000236000	SCV000292996	uncertain significance	not provided	2015-08-05	criteria provided, single submitter	clinical testing	The A432V variant in the IGHMBP2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The A432V variant was not observed at any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common variant in these populations. The A432V variant is a conservative amino acid substitution, which occurs at a position that is not conserved across species. In silico analysis predicts this variant likely does not alter the protein structure/function. We interpret A432V as a variant of unknown significance.
Fulgent Genetics,Fulgent Genetics	RCV000763763	SCV000894658	uncertain significance	Spinal muscular atrophy, distal, autosomal recessive, 1; Charcot-Marie-Tooth disease, axonal, type 2S	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV000763763	SCV000956167	uncertain significance	Spinal muscular atrophy, distal, autosomal recessive, 1; Charcot-Marie-Tooth disease, axonal, type 2S	2018-08-22	criteria provided, single submitter	clinical testing	This sequence change replaces alanine with valine at codon 432 of the IGHMBP2 protein (p.Ala432Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs370414354, 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: 245837). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.