ClinVar Miner

Submissions for variant NM_002180.2(IGHMBP2):c.1478C>T (p.Thr493Ile) (rs780594709)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Department of Medical Genetics, Oslo University Hospital RCV000240667 SCV000255977 likely pathogenic Spinal muscular atrophy, distal, autosomal recessive, 1 2015-10-21 criteria provided, single submitter research
Department of Medical Genetics, Oslo University Hospital RCV000240662 SCV000255979 likely pathogenic Charcot-Marie-Tooth disease, axonal, type 2S 2015-10-21 criteria provided, single submitter research
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000223974 SCV000281133 pathogenic not provided 2017-10-05 criteria provided, single submitter clinical testing
GeneDx RCV000223974 SCV000322437 pathogenic not provided 2016-12-22 criteria provided, single submitter clinical testing The T493I pathogenic variant in the IGHMBP2 gene has been reported previously in the compound heterozygous state with other pathogenic IGHMBP2 variants in multiple individuals with both infantile-onset and juvenile-onset SMARD1 (Guenther et al., 2009; Hamilton et al., 2015). Functional studies demonstrate that the T493I variant has an increased tendency to aggregate and spontaneously degrade in vitro (Guenther et al., 2009). The T493I variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The T493I variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties, and occurs at a position that is conserved across species. Additionally, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, T493I is interpreted to be a pathogenic variant.
Invitae RCV000693518 SCV000821389 pathogenic Spinal muscular atrophy, distal, autosomal recessive, 1; Charcot-Marie-Tooth disease, axonal, type 2S 2018-03-28 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 493 of the IGHMBP2 protein (p.Thr493Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs780594709, ExAC 0.02%). This variant has been observed on the opposite chromosome (in trans) from other pathogenic variants in individuals affected with spinal muscular atrophy with respiratory distress, type 1 (SMARD1) or Charcot-Marie-Tooth disease, type 2S (CMT2S) (PMID: 18802676, 27450922, Invitae). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. This variant has been reported to segregate with SMARD1 or CMT2S in families (PMID: 27450922, 19157874) and has been reported in combination with another IGHMBP2 variant in individuals affected with SMARD1 (PMID: 25454169). ClinVar contains an entry for this variant (Variation ID: 217450). Experimental studies have shown that this missense change results in an IGHMBP2 protein with ATPase and helicase activity indistinguishable from the wildtype protein, however RNA and DNA binding is diminished, and the protein has altered physiochemical properties, a tendency to form aggregates, and is unstable in vitro (PMID: 18802676, 19158098). For these reasons, this variant has been classified as Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000240667 SCV000914536 pathogenic Spinal muscular atrophy, distal, autosomal recessive, 1 2018-10-18 criteria provided, single submitter clinical testing The IGHMBP2 c.1478C>T (p.Thr493Ile) missense variant has been reported in at least five studies in which it was identified in a compound heterozygous state in seven individuals from five families with spinal muscular atrophy (Guenther et al. 2009; Joseph et al. 2009; Eckart et al. 2012; Hamilton et al. 2015; Pedurupillay et al. 2016). In one sibling pair who carried a small deletion in trans with the p.Thr493Ile variant, one individual exhibited a more classic infantile spinal muscular atrophy phenotype while the other showed a phenotype consistent with Charcot-Marie-Tooth type 2S (Pedurupillay et al. 2016). However, the p.Thr493Ile variant was not identified in 11 probands with Charcot-Marie-Tooth type 2 who had recessively inherited IGHMBP2 variants (Cottenie et al. 2014). The variant p.Thr493Ile was absent from 300 control individuals (Guenther et al. 2009) and is reported at a frequency of 0.00025 in the European (non-Finnish) population of the Exome Aggregation Consortium. Expression of the variant in E. coli showed that it did not influence IGHMBP2 ATPase or helicase activity compared to wild type values (Guenther et al. 2009b), consistent with its location distant from helicase motifs. Comparison of steady-state IGHMBP2 protein levels in probands and their heterozygous parents indicated the p.Thr493Ile variant reduced steady-state protein levels by 50% compared to wild type levels (Guenther et al. 2009), and qRT-PCR experiments indicated the variant did not result in nonsense-mediated decay (Pedurupillay et al. 2016). Based on the collective evidence, the p.Thr493Ile variant is classified as pathogenic for spinal muscular atrophy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Mayo Clinic Laboratories, Mayo Clinic RCV000223974 SCV001716106 pathogenic not provided 2020-01-17 criteria provided, single submitter clinical testing PS3, PS4_moderate, PM2, PM3, PP3
Inherited Neuropathy Consortium RCV000789340 SCV000928693 uncertain significance Autosomal dominant distal hereditary motor neuropathy no assertion criteria provided literature only

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