Submissions for variant NM_002180.3(IGHMBP2):c.2911_2912del (p.Arg971fs)

dbSNP: rs724159994

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000221709	SCV000278984	pathogenic	not provided	2022-09-16	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation as the last 23 amino acids are lost and replaced with 3 incorrect amino acids; This variant is associated with the following publications: (PMID: 26298607, 30373780, 31827005, 33084218, 32376792, 26392352)
Invitae	RCV000552806	SCV000642356	pathogenic	Autosomal recessive distal spinal muscular atrophy 1; Charcot-Marie-Tooth disease axonal type 2S	2024-01-23	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg971Glufs*4) in the IGHMBP2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 23 amino acid(s) of the IGHMBP2 protein. This variant is present in population databases (rs572973851, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with peripheral neuropathy (PMID: 15269181, 25439726, 25568292, 26392352; Invitae). ClinVar contains an entry for this variant (Variation ID: 162195). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000624736	SCV000741688	pathogenic	Inborn genetic diseases	2021-05-14	criteria provided, single submitter	clinical testing	The c.2911_2912delAG (p.R971Efs*4) alteration, located in exon 15 (coding exon 15) of the IGHMBP2 gene, consists of a deletion of 2 nucleotides from position 2911 to 2912, causing a translational frameshift with a predicted alternate stop codon after 4 amino acids. This alteration occurs at the 3' terminus of the IGHMBP2 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 23 amino acids of the protein. However, premature stop codons are typically deleterious in nature. Based on data from gnomAD, this allele has an overall frequency of 0.012% (33/279672) total alleles studied. The highest observed frequency was 0.024% (31/127458) of European (non-Finnish) alleles. This variant has been reported in conjunction with other pathogenic mutations in IGHMBP2 in multiple unrelated patients with IGHMBP2-related neuropathy (Cottenie, 2014; Bacquet, 2018; Cortese, 2020; Schottmann, 2015). This alteration has also been detected in the homozygous state in a patient reported to have Charcot-Marie-Tooth disease; however, clinical information was limited (Antoniadi, 2015). Based on the available evidence, this alteration is classified as pathogenic.
Molecular Genetics Laboratory, London Health Sciences Centre	RCV000192260	SCV001335629	likely pathogenic	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Consultorio y Laboratorio de Neurogenética, Hospital JM Ramos Mejia	RCV001261534	SCV001424043	pathogenic	Autosomal recessive distal spinal muscular atrophy 1		criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000221709	SCV002023143	pathogenic	not provided	2019-07-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000149575	SCV004122861	pathogenic	Charcot-Marie-Tooth disease axonal type 2S	2023-10-13	criteria provided, single submitter	clinical testing	Variant summary: IGHMBP2 c.2911_2912delAG (p.Arg971GlufsX4) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein. The variant allele was found at a frequency of 0.00012 in 248290 control chromosomes (gnomAD). c.2911_2912delAG has been reported in the literature in individuals affected with Charcot-Marie Tooth disease type 2 (examples: Bacquet_2018, Cottenie_2014). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 30373780, 31827005). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variants as pathogenic (n=4) and VUS (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000221709	SCV004227239	likely pathogenic	not provided	2022-07-22	criteria provided, single submitter	clinical testing	PP1, PM2, PM3_strong, PVS1_moderate
OMIM	RCV000149575	SCV000196551	pathogenic	Charcot-Marie-Tooth disease axonal type 2S	2015-02-03	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
Clinical Genetics, Academic Medical Center	RCV000221709	SCV001923791	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000221709	SCV001926844	pathogenic	not provided		no assertion criteria provided	clinical testing