ClinVar Miner

Submissions for variant NM_002180.2(IGHMBP2):c.1336C>T (p.Gln446Ter) (rs372181708)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000760424 SCV000890305 pathogenic not provided 2020-05-20 criteria provided, single submitter clinical testing Identified in a patient with spinal muscular atrophy with respiratory distress in published literature (Jedrzejowska et al., 2014); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 24388491)
Invitae RCV000791593 SCV000930850 pathogenic Spinal muscular atrophy, distal, autosomal recessive, 1; Charcot-Marie-Tooth disease, axonal, type 2S 2019-10-17 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln446*) in the IGHMBP2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs372181708, ExAC 0.002%). This variant has been observed in an individual affected with spinal muscular atrophy with respiratory distress type 1 (SMARD1) (PMID: 24388491). Loss-of-function variants in IGHMBP2 are known to be pathogenic (PMID: 14681881, 25439726, 25568292). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000826144 SCV000967674 pathogenic Distal spinal muscular atrophy 2018-07-18 criteria provided, single submitter clinical testing The p.Gln446X variant in IGHMBP2 has been previously reported in one compound he terozygous individual with spinal muscular atrophy with respiratory distress (SM ARD1) who also carried a de novo missense allele (Jedrzejowska 2014). This varia nt has been identified in 3/110614 European chromosomes by the Genome Aggregatio n Database (gnomAD,; dbSNP rs372181708). This n onsense variant leads to a premature termination codon at position 446, which is predicted to lead to a truncated or absent protein. Complete loss of IGHMBP2 fu nction is an established disease mechanism for SMARD1. In summary, this variant meets criteria to be classified as pathogenic for SMARD1 in an autosomal recessi ve manner. ACMG/AMP criteria applied: PVS1, PM3_Supporting, PM2.
Inherited Neuropathy Consortium RCV000789344 SCV000928697 uncertain significance Autosomal dominant distal hereditary motor neuropathy no assertion criteria provided literature only

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