rs780594709
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_002180.3(IGHMBP2):c.1478C>T(p.Thr493Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000771 in 1,608,422 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_002180.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152148Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000631 AC: 15AN: 237608Hom.: 0 AF XY: 0.0000388 AC XY: 5AN XY: 128840
GnomAD4 exome AF: 0.0000824 AC: 120AN: 1456274Hom.: 0 Cov.: 31 AF XY: 0.0000718 AC XY: 52AN XY: 723830
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152148Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74326
ClinVar
Submissions by phenotype
not provided Pathogenic:4
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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) -
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PS3, PS4_moderate, PM2, PM3, PP3 -
Autosomal recessive distal spinal muscular atrophy 1 Pathogenic:3
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. -
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Autosomal recessive distal spinal muscular atrophy 1;C4015349:Charcot-Marie-Tooth disease axonal type 2S Pathogenic:2
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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; internal data). 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). Invitae Evidence 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 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. -
Inborn genetic diseases Pathogenic:1
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. -
Charcot-Marie-Tooth disease axonal type 2S Pathogenic:1
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Neuronopathy, distal hereditary motor, autosomal dominant Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at