Submissions for variant NM_002180.2(IGHMBP2):c.2837G>A (p.Arg946Gln) (rs149824485)

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000236700	SCV000294162	uncertain significance	not provided	2017-10-19	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the IGHMBP2 gene. The R946Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R946Q variant is observed in 159/126,180 (0.1%) alleles from individuals of European background (Lek et al., 2016). The R946Q variant is a semi-conservative amino acidsubstitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position where amino acids with similar properties to Arginine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is 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.
Illumina Clinical Services Laboratory,Illumina	RCV000292250	SCV000373811	uncertain significance	Spinal muscular atrophy	2016-06-14	criteria provided, single submitter	clinical testing
Invitae	RCV000556244	SCV000642353	uncertain significance	Spinal muscular atrophy, distal, autosomal recessive, 1; Charcot-Marie-Tooth disease, axonal, type 2S	2018-11-06	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with glutamine at codon 946 of the IGHMBP2 protein (p.Arg946Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs149824485, ExAC 0.1%). This variant has not been reported in the literature in individuals with IGHMBP2-related disease. ClinVar contains an entry for this variant (Variation ID: 246570). 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.
Athena Diagnostics Inc	RCV000236700	SCV001144479	likely benign	not provided	2019-02-27	criteria provided, single submitter	clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000236700	SCV001148364	uncertain significance	not provided	2019-05-01	criteria provided, single submitter	clinical testing