Submissions for variant NM_002180.3(IGHMBP2):c.830A>G (p.Gln277Arg)

gnomAD frequency: 0.00001  dbSNP: rs112495985

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000442407	SCV000534416	uncertain significance	not provided	2016-12-02	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the IGHMBP2 gene. The Q277R variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The Q277R variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The Q277R variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Additionally, this substitution is predicted to be within the helicase domain (Lim et al., 2012; Cottenie et al., 2014; Jedrzejowska et al., 2014). However, this substitution occurs at a position that is not conserved. 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.
Invitae	RCV000703580	SCV000832486	uncertain significance	Autosomal recessive distal spinal muscular atrophy 1; Charcot-Marie-Tooth disease axonal type 2S	2021-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine with arginine at codon 277 of the IGHMBP2 protein (p.Gln277Arg). The glutamine residue is weakly conserved and there is a small physicochemical difference between glutamine and arginine. This variant is present in population databases (rs112495985, ExAC 0.03%). This variant has not been reported in the literature in individuals affected with IGHMBP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 391360). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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.
CeGaT Center for Human Genetics Tuebingen	RCV000442407	SCV004702804	likely benign	not provided	2024-04-01	criteria provided, single submitter	clinical testing	IGHMBP2: BP4
GenomeConnect - Invitae Patient Insights Network	RCV000703580	SCV004228600	not provided	Autosomal recessive distal spinal muscular atrophy 1; Charcot-Marie-Tooth disease axonal type 2S		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 03-15-2018 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.