Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000412903 | SCV000492370 | likely pathogenic | not provided | 2016-12-12 | criteria provided, single submitter | clinical testing | A novel c.547+1 G>A variant that is likely pathogenic has been identified in the IGHMBP2 gene. The c.547+1 G>A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.547+1 G>A variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The c.547+1 G>A splice site variant in the IGHMBP2 gene destroys the canonical splice donor site in intron 4. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. |
| Labcorp Genetics |
RCV000642629 | SCV000764316 | pathogenic | Autosomal recessive distal spinal muscular atrophy 1; Charcot-Marie-Tooth disease axonal type 2S | 2024-07-01 | criteria provided, single submitter | clinical testing | This sequence change affects a donor splice site in intron 4 of the IGHMBP2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in IGHMBP2 are known to be pathogenic (PMID: 14681881, 25439726, 25568292). This variant is present in population databases (no rsID available, gnomAD 0.006%). Disruption of this splice site has been observed in individual(s) with clinical features of IGHMBP2-related conditions (PMID: 28902413, 31019026; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 373749). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. |
| Service de Pédiatrie - |
RCV000754569 | SCV000863995 | likely pathogenic | Autosomal recessive distal spinal muscular atrophy 1 | 2018-01-21 | criteria provided, single submitter | case-control | It is a splice mutation (at the beginning of intron 4, hence probably on a splice site), whose dysfunction might generate a premature stop codon. It occurs early in the sequence: in the intron 4, for a total of 15 exons. Moreover, it is located in the main functional domain "DNA helicase domain" of the protein IGHMB2, at a specific location where ATP binding sites are concentrated. |
| Rady Children's Institute for Genomic Medicine, |
RCV000754569 | SCV000996093 | likely pathogenic | Autosomal recessive distal spinal muscular atrophy 1 | 2017-12-19 | criteria provided, single submitter | clinical testing | This splice variant is predicted to impact a canonical splice donor site. This variant has been classified by a clinical laboratory as likely pathogenic in ClinVar (Variation ID 373749). This variant has not been previously reported literature nor has it been functionally characterized to our knowledge; however, several other splice variants in this gene have been previously described in association with disease. Multiple in silico splice prediction tools predict a damaging effect of the variant. It is present in the heterozygous state in the gnomAD population database at a frequency of 0.003% (1/30934). Based on the combined evidence, the c.547+1G>A is classified as likely pathogenic. |
| Ce |
RCV000412903 | SCV002062994 | pathogenic | not provided | 2024-03-01 | criteria provided, single submitter | clinical testing | IGHMBP2: PVS1, PM2, PM3 |