Submissions for variant NM_002180.3(IGHMBP2):c.1478C>T (p.Thr493Ile)

gnomAD frequency: 0.00003  dbSNP: rs780594709

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Department of Medical Genetics, Oslo University Hospital	RCV000240667	SCV000255977	likely pathogenic	Autosomal recessive distal spinal muscular atrophy 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	2021-09-27	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19157874, 19158098, 22965130, 25439726, 27450922, 31827005, 18802676, 25454169)
Invitae	RCV000693518	SCV000821389	pathogenic	Autosomal recessive distal spinal muscular atrophy 1; Charcot-Marie-Tooth disease axonal type 2S	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 493 of the IGHMBP2 protein (p.Thr493Ile). This variant is present in population databases (rs780594709, gnomAD 0.01%). This missense change has been observed in individual(s) with spinal muscular atrophy with respiratory distress, type 1 or Charcot-Marie-Tooth disease, type 2S (PMID: 18802676, 19157874, 25454169, 27450922; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 217450). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on IGHMBP2 protein function. Experimental studies have shown that this missense change affects IGHMBP2 function (PMID: 18802676, 19158098). For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina	RCV000240667	SCV000914536	pathogenic	Autosomal recessive distal spinal muscular atrophy 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
Revvity Omics, Revvity	RCV000223974	SCV002023148	pathogenic	not provided	2019-01-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002390539	SCV002701125	pathogenic	Inborn genetic diseases	2020-01-09	criteria provided, single submitter	clinical testing	The p.T493I pathogenic mutation (also known as c.1478C>T), located in coding exon 10 of the IGHMBP2 gene, results from a C to T substitution at nucleotide position 1478. The threonine at codon 493 is replaced by isoleucine, an amino acid with similar properties. This alteration has been detected in trans with pathogenic mutations in IGHMBP2 in multiple affected individuals (Guenther UP et al. J. Mol. Med., 2009 Jan;87:31-41; Pedurupillay CR et al. Neuromuscul. Disord., 2016 09;26:570-5; Hamilton MJ et al. Neuromuscul. Disord., 2015 Feb;25:169-71). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Baylor Genetics	RCV000240667	SCV003836130	pathogenic	Autosomal recessive distal spinal muscular atrophy 1	2022-01-20	criteria provided, single submitter	clinical testing
Inherited Neuropathy Consortium	RCV000789340	SCV000928693	uncertain significance	Neuronopathy, distal hereditary motor, autosomal dominant		no assertion criteria provided	literature only