ClinVar Miner

Submissions for variant NM_002180.2(IGHMBP2):c.2909_2910AG[1] (p.Arg971fs) (rs724159994)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000221709 SCV000278984 pathogenic not provided 2018-12-12 criteria provided, single submitter clinical testing TThe c.2911_2912delAG pathogenic variant in the IGHMBP2 gene has been previously reported in individuals with axonal neuropathy who also had a pathogenic variant on the opposite IGHMBP2 allele (Cottenie et al., 2014; Schottmann et al., 2015). The c.2911_2912delAG variant is observed in 31/125242 (0.03%) alleles from individuals of European background (Lek et al., 2016). The c.2911_2912delAG variant causes a frameshift starting with codon Arginine 971, changes this amino acid to a Glutamic acid residue and creates a premature Stop codon at position 4 of the new reading frame, denoted p.Arg971GlufsX4. This variant is predicted to cause loss of normal protein function through protein truncation as the last 23 amino acids are replaced with 3 incorrect residues. Therefore, we interpret c.2911_2912delAG as a pathogenic variant.
Invitae RCV000552806 SCV000642356 pathogenic Spinal muscular atrophy, distal, autosomal recessive, 1; Charcot-Marie-Tooth disease, axonal, type 2S 2018-11-12 criteria provided, single submitter clinical testing This sequence change deletes 2 nucleotides from exon 15 of the IGHMBP2 mRNA (c.2911_2912delAG), causing a frameshift at codon 971. This creates a premature translational stop signal in the last exon of the IGHMBP2 mRNA (p.Arg971Glufs*4). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 19 amino acids of the IGHMBP2 protein. This variant is present in population databases (rs572973851, ExAC 0.03%). Loss of function variants in IGHMBP2 are known to be pathogenic (PMID: 15269181). This variant has been reported in the homozygous state in an individual affected with peripheral neuropathy (PMID: 26392352). This variant has also been identified in the compound heterozygous state with a second truncating IGHMBP2 variant in patients affected with sensorimotor neuropathy (PMID: 25568292) and in patients affected with Charcot-Marie-Tooth disease type 2 (CMT2) (PMID: 25439726, Invitae database). ClinVar contains an entry for this variant (Variant ID: 162195). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000624736 SCV000741688 likely pathogenic Inborn genetic diseases 2016-08-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: LIKELY POSITIVE: Relevant Alteration(s) Detected
OMIM RCV000149575 SCV000196551 pathogenic Charcot-Marie-Tooth disease, axonal, type 2S 2015-02-03 no assertion criteria provided literature only
GeneReviews RCV000192260 SCV000239908 pathogenic Charcot-Marie-Tooth disease 2015-04-30 no assertion criteria provided literature only
Institute of Human Genetics,Cologne University RCV000664248 SCV000787816 uncertain significance Distal spinal muscular atrophy 2018-04-26 no assertion criteria provided clinical testing
Inherited Neuropathy Consortium RCV000192260 SCV000929747 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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