Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Illumina Laboratory Services, |
RCV001112398 | SCV001270055 | uncertain significance | Autosomal recessive distal spinal muscular atrophy 1 | 2018-01-13 | criteria provided, single submitter | clinical testing | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. |
| ARUP Laboratories, |
RCV002227248 | SCV002506272 | uncertain significance | not provided | 2022-02-05 | criteria provided, single submitter | clinical testing | The IGHMBP2 c.1816C>T; p.Arg606Cys variant (rs536556753), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 882605). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 606 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.724). Additionally, another variant at this codon (c.1817G>A; p.Arg606His) has been reported in the compound heterozygous state in an individual with spinal muscular atrophy (Lin 2014). However, given the lack of clinical and functional data, the significance of the p.Arg606Cys variant is uncertain at this time. References: Lin X et al. Variations of IGHMBP2 gene was not the major cause of Han Chinese patients with non-5q-spinal muscular atrophies. J Child Neurol. 2014 Aug;29(8):NP35-9. PMID: 24022109. |
| Invitae | RCV002558121 | SCV003293206 | uncertain significance | Autosomal recessive distal spinal muscular atrophy 1; Charcot-Marie-Tooth disease axonal type 2S | 2022-04-12 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 606 of the IGHMBP2 protein (p.Arg606Cys). This variant is present in population databases (rs536556753, gnomAD 0.007%). 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: 882605). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Arg606 amino acid residue in IGHMBP2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24022109). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. |
| Revvity Omics, |
RCV002227248 | SCV003813285 | uncertain significance | not provided | 2020-11-12 | criteria provided, single submitter | clinical testing |