Submissions for variant NM_002180.2(IGHMBP2):c.165G>C (p.Gln55His) (rs201692151)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000489846	SCV000577545	uncertain significance	not provided	2017-03-21	criteria provided, single submitter	clinical testing	The Q55H variant has been reported previously in the heterozygous state in an individual with CMT2 and spasticity who also had variants in two other genes that may have been responsible for the phenotype; therefore, the authors conclude that Q55H is not pathogenic (Høyer et al., 2014). The Q55H variant is observed in 14/6614 (0.2%) alleles from individuals of Finnish background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The Q55H variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved 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 or a rare benign variant.
Invitae	RCV000558992	SCV000642316	uncertain significance	Spinal muscular atrophy, distal, autosomal recessive, 1; Charcot-Marie-Tooth disease, axonal, type 2S	2018-05-14	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine with histidine at codon 55 of the IGHMBP2 protein (p.Gln55His). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and histidine. This variant is present in population databases (rs201692151, ExAC 0.2%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals with IGHMBP2-related disease. ClinVar contains an entry for this variant (Variation ID: 426960). 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: "Tolerated"; PolyPhen-2: "Probably 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.