ClinVar Miner

Submissions for variant NM_002180.2(IGHMBP2):c.1273C>T (p.Arg425Cys) (rs1303837541)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000806743 SCV000946758 uncertain significance Spinal muscular atrophy, distal, autosomal recessive, 1; Charcot-Marie-Tooth disease, axonal, type 2S 2019-02-25 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 425 of the IGHMBP2 protein (p.Arg425Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with spinal muscular atrophy with respiratory distress (PMID: 22791546). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000853264 SCV000996092 likely pathogenic Spinal muscular atrophy, distal, autosomal recessive, 1 2017-12-19 criteria provided, single submitter clinical testing This variant was previously reported in a compound heterozygous state in an infant with infantile spinal muscular atrophy with respiratory distress type 1 (PMID: 22791546). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0012% (3/246146). This variant has not been functionally characterized to our knowledge. However, multiple in silico analysis predict the variant to be damaging. Based on the combined evidence, the p.Gly260Arg variant is classified as likely pathogenic.
Victorian Clinical Genetics Services,Murdoch Childrens Research Institute RCV000853264 SCV001245042 pathogenic Spinal muscular atrophy, distal, autosomal recessive, 1 2019-01-11 criteria provided, single submitter clinical testing A heterozygous missense variant, NM_002180.2(IGHMBP2):c.1273C>T, has been identified in exon 9 of 15 of the IGHMBP2 gene. The variant is predicted to result in a major amino acid change from arginie to cysteine at position 425 of the protein (NP_002171.2(IGHMBP2):p.(Arg425Cys)). The arginine residue at this position has high conservation (100 vertebrates, UCSC), and is located within the Helicase functional domain. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.0011% (3 heterozygotes, 0 homozygotes). An alternative residue change has been reported in the gnomAD database at a frequency of 0.0024% (3 heterozygoes, 0 homozygotes). The variant has been previously described as pathogenic in a patient with diaphragmatic weakness with progressive sensory and motor polyneuropathy (Gitiaux et al., (2012)). A different variant in the same codon resulting in a change to histidine has been reported as a Variant of Uncertain Significance (ClinVar). Analysis of parental samples indicated this variant was maternally inherited. Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.
Molecular Genetics Laboratory,London Health Sciences Centre RCV000789974 SCV001336676 uncertain significance Charcot-Marie-Tooth disease criteria provided, single submitter clinical testing
Inherited Neuropathy Consortium RCV000789974 SCV000929363 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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