Submissions for variant NM_002180.2(IGHMBP2):c.761G>A (p.Arg254His) (rs761191746)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000235714	SCV000294155	uncertain significance	not provided	2016-05-11	criteria provided, single submitter	clinical testing	The R254H variant has 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. The R254H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and missense variants in nearby residues (L251P; A256G) have been reported in the Human Gene Mutation Database in association with IGHMBP2-related disorders (Stenson et al., 2014). Additionally, in silico analysis predicts this variant is probably 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	RCV000696905	SCV000825486	uncertain significance	Spinal muscular atrophy, distal, autosomal recessive, 1; Charcot-Marie-Tooth disease, axonal, type 2S	2018-03-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with histidine at codon 254 of the IGHMBP2 protein (p.Arg254His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs761191746, ExAC 0.001%). This variant has not been reported in the literature in individuals with IGHMBP2-related disease. ClinVar contains an entry for this variant (Variation ID: 246563). 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"). 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.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000790913	SCV000930160	uncertain significance	not specified	2019-04-27	criteria provided, single submitter	clinical testing