Submissions for variant NM_002180.3(IGHMBP2):c.138T>A (p.Cys46Ter)

gnomAD frequency: 0.00001  dbSNP: rs372000714

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255598	SCV000321772	pathogenic	not provided	2023-01-11	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 14681881, 33210134, 34426522, 25439726, 25568292)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000550952	SCV000642304	pathogenic	Autosomal recessive distal spinal muscular atrophy 1; Charcot-Marie-Tooth disease axonal type 2S	2023-12-12	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Cys46*) in the IGHMBP2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in IGHMBP2 are known to be pathogenic (PMID: 14681881, 25439726, 25568292). This variant is present in population databases (rs372000714, gnomAD 0.004%). This premature translational stop signal has been observed in individuals with spinal muscular atrophy with respiratory distress 1 and Charcot-Marie-Tooth disease type 2 (PMID: 14681881, 25439726, 25568292). ClinVar contains an entry for this variant (Variation ID: 162194). For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000995566	SCV001149808	pathogenic	Autosomal recessive distal spinal muscular atrophy 1	2018-08-14	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000995566	SCV001368450	pathogenic	Autosomal recessive distal spinal muscular atrophy 1	2020-03-31	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS4,PM2,PM3. This variant was detected in homozygous state.
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001814070	SCV001755567	pathogenic	Peripheral neuropathy	2021-07-10	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002390316	SCV002698376	pathogenic	Inborn genetic diseases	2021-05-11	criteria provided, single submitter	clinical testing	The p.C46* pathogenic mutation (also known as c.138T>A), located in coding exon 2 of the IGHMBP2 gene, results from a T to A substitution at nucleotide position 138. This changes the amino acid from a cysteine to a stop codon within coding exon 2. This variant was detected as compound heterozygous with another mutation in IGHMBP2 in multiple individuals with Charcot-Marie-Tooth disease type 2 (Cottenie E et al. Am J Hum Genet, 2014 Nov;95:590-601; Schottmann G et al. Neurology, 2015 Feb;84:523-31). This variant was also detected in an individual with distal spinal muscular atrophy 1 with respiratory distress (SMARD1) (Grohmann K et al. Ann Neurol, 2003 Dec;54:719-24). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000995566	SCV003761314	pathogenic	Autosomal recessive distal spinal muscular atrophy 1	2023-01-25	criteria provided, single submitter	curation	The heterozygous p.Cys46Ter variant in IGHMBP2 was identified by our study, in the compound heterozygous state with a variant of uncertain significance (dbSNP ID: rs1449942315), in one individual with distal spinal muscular atrophy. This individual also carried a variant of uncertain significance (dbSNP ID: rs1449942315); however, the phase of these variants are unknown at this time. The p.Cys46Ter variant in IGHMBP2 has been previously reported in 5 unrelated individuals with autosomal recessive IGHMBP2-related neurological disease (PMID: 25568292, PMID: 25439726, PMID: 14681881) and segregated with disease in 7 affected relatives from 4 families (PMID: 25439726, PMID: 25568292), but has been identified in 0.0035% (4/113764) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs372000714). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. Of these 5 affected individuals (PMID: 25568292, PMID: 25439726, PMID: 14681881), 4 were compound heterozygotes who carried pathogenic or likely pathogenic variants in trans (PMID: 25568292, ClinVar Variation ID: 162195; PMID: 25439726, ClinVar Variation ID: 162195; PMID: 14681881), which increases the likelihood that the p.Cys46Ter variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 162194) and has been interpreted as pathogenic by multiple submitters. This nonsense variant leads to a premature termination codon at position 46, which is predicted to lead to a truncated or absent protein. Loss of function of the IGHMBP2 gene is strongly associated to autosomal recessive distal spinal muscular atrophy 1. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive distal spinal muscular atrophy 1. ACMG/AMP Criteria applied: PVS1_Strong, PM2_Supporting, PM3_VeryStrong, PP1_Moderate (Richards 2015).
OMIM	RCV000149574	SCV000196550	pathogenic	Charcot-Marie-Tooth disease axonal type 2S	2015-02-03	no assertion criteria provided	literature only
Inherited Neuropathy Consortium	RCV000790277	SCV000929681	uncertain significance	Distal spinal muscular atrophy		no assertion criteria provided	literature only
Clinical Genetics, Academic Medical Center	RCV000255598	SCV001922331	pathogenic	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000255598	SCV001963176	pathogenic	not provided		no assertion criteria provided	clinical testing