Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Molecular Genetics Laboratory, |
RCV001173560 | SCV001336657 | uncertain significance | Charcot-Marie-Tooth disease | criteria provided, single submitter | clinical testing | ||
Invitae | RCV001308875 | SCV001498350 | uncertain significance | Autosomal recessive distal spinal muscular atrophy 1; Charcot-Marie-Tooth disease axonal type 2S | 2021-08-28 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine with methionine at codon 535 of the IGHMBP2 protein (p.Ile535Met). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with IGHMBP2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The methionine 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. |
ARUP Laboratories, |
RCV001811681 | SCV002048081 | uncertain significance | not provided | 2021-10-14 | criteria provided, single submitter | clinical testing | The IGHMBP2 c.1605T>G; p.Ile535Met variant (rs1225363387) is reported in the literature in an individual affected with Charcot-Marie-Tooth disease, although its clinical significance was considered uncertain (Volodarsky 2021). This variant is found on a single chromosome in the Genome Aggregation Database (1/247364 alleles), indicating it is not a common polymorphism. The isoleucine at codon 535 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.518). Due to limited information, the clinical significance of the p.Ile535Met variant is uncertain at this time. References: Volodarsky M et al. Comprehensive genetic sequence and copy number analysis for Charcot-Marie-Tooth disease in a Canadian cohort of 2517 patients. J Med Genet. 2021 Apr;58(4):284-288. PMID: 32376792. |