ClinVar Miner

Submissions for variant NM_002180.2(IGHMBP2):c.547+1G>A (rs1057518588)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx 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.
Invitae RCV000642629 SCV000764316 likely pathogenic Spinal muscular atrophy, distal, autosomal recessive, 1; Charcot-Marie-Tooth disease, axonal, type 2S 2019-06-21 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 and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in the heterozygous state in an individual affected with hereditary neuropathy (PMID: 28902413). 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, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants 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). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Service de Pédiatrie - Neurologie et infectiologie - Toulouse,CHU de Toulouse - Hôpital des Enfants RCV000754569 SCV000863995 likely pathogenic Spinal muscular atrophy, distal, autosomal recessive, 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, Rady Children's Hospital San Diego RCV000754569 SCV000996093 likely pathogenic Spinal muscular atrophy, distal, autosomal recessive, 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.

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