Submissions for variant NM_002180.3(IGHMBP2):c.440G>A (p.Arg147Gln)

gnomAD frequency: 0.00006  dbSNP: rs138448914

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000822234	SCV000963026	uncertain significance	Autosomal recessive distal spinal muscular atrophy 1; Charcot-Marie-Tooth disease axonal type 2S	2022-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 147 of the IGHMBP2 protein (p.Arg147Gln). This variant is present in population databases (rs138448914, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of IGHMBP2-related conditions (PMID: 32376792). ClinVar contains an entry for this variant (Variation ID: 664193). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt IGHMBP2 protein function. 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.
Molecular Genetics Laboratory, London Health Sciences Centre	RCV001173566	SCV001336663	uncertain significance	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
GeneDx	RCV001766741	SCV001999188	uncertain significance	not provided	2019-10-21	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 32376792)
Ambry Genetics	RCV002332712	SCV002631880	uncertain significance	Inborn genetic diseases	2022-08-24	criteria provided, single submitter	clinical testing	The p.R147Q variant (also known as c.440G>A), located in coding exon 3 of the IGHMBP2 gene, results from a G to A substitution at nucleotide position 440. The arginine at codon 147 is replaced by glutamine, an amino acid with highly similar properties. This variant was detected in a Charcot-Marie-Tooth disease cohort; however, clinical details were limited (Volodarsky M et al. J Med Genet, 2021 04;58:284-288). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
CeGaT Center for Human Genetics Tuebingen	RCV001766741	SCV004701674	uncertain significance	not provided	2024-02-01	criteria provided, single submitter	clinical testing	IGHMBP2: PM2