ClinVar Genomic variation as it relates to human health
NM_002180.3(IGHMBP2):c.138T>A (p.Cys46Ter)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_002180.3(IGHMBP2):c.138T>A (p.Cys46Ter)
Variation ID: 162194 Accession: VCV000162194.40
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q13.3 11: 68906120 (GRCh38) [ NCBI UCSC ] 11: 68673588 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Oct 5, 2015 May 1, 2024 Dec 12, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002180.3:c.138T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002171.2:p.Cys46Ter nonsense NC_000011.10:g.68906120T>A NC_000011.9:g.68673588T>A NG_007976.1:g.7270T>A LRG_250:g.7270T>A LRG_250t1:c.138T>A - Protein change
- Other names
- C46*
- NM_002180.3(IGHMBP2):c.138T>A
- p.Cys46Ter
- Canonical SPDI
- NC_000011.10:68906119:T:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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IGHMBP2 | - | - |
GRCh38 GRCh37 |
1321 | 1400 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
no assertion criteria provided
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Feb 3, 2015 | RCV000149574.7 | |
Pathogenic (3) |
criteria provided, single submitter
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Jan 11, 2023 | RCV000255598.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 12, 2023 | RCV000550952.8 | |
Uncertain significance (1) |
no assertion criteria provided
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- | RCV000790277.1 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 25, 2023 | RCV000995566.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 10, 2021 | RCV001814070.1 | |
Pathogenic (1) |
criteria provided, single submitter
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May 11, 2021 | RCV002390316.2 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Aug 14, 2018)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive distal spinal muscular atrophy 1
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV001149808.1
First in ClinVar: Feb 03, 2020 Last updated: Feb 03, 2020 |
Sex: male
Tissue: blood
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Pathogenic
(Mar 31, 2020)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive distal spinal muscular atrophy 1
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001368450.2
First in ClinVar: Jul 06, 2020 Last updated: Dec 12, 2020 |
Comment:
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.
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Pathogenic
(Jul 10, 2021)
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criteria provided, single submitter
Method: clinical testing
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Peripheral neuropathy
Affected status: yes
Allele origin:
germline
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Kariminejad - Najmabadi Pathology & Genetics Center
Accession: SCV001755567.1
First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022 |
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Pathogenic
(Jan 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000321772.9
First in ClinVar: Oct 09, 2016 Last updated: Jan 21, 2023 |
Comment:
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 … (more)
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) (less)
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Pathogenic
(Dec 12, 2023)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive distal spinal muscular atrophy 1
Charcot-Marie-Tooth disease axonal type 2S
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000642304.6
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(May 11, 2021)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002698376.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Jan 25, 2023)
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criteria provided, single submitter
Method: curation
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Autosomal recessive distal spinal muscular atrophy 1
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV003761314.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
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), … (more)
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). (less)
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Pathogenic
(Feb 03, 2015)
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no assertion criteria provided
Method: literature only
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CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2S
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000196550.5
First in ClinVar: Jan 11, 2015 Last updated: Oct 13, 2016 |
Comment on evidence:
In 3 English patients, including 2 sisters, with childhood-onset Charcot-Marie-Tooth disease type 2S (CMT2S; 616155), Cottenie et al. (2014) identified compound heterozygous mutations in the … (more)
In 3 English patients, including 2 sisters, with childhood-onset Charcot-Marie-Tooth disease type 2S (CMT2S; 616155), Cottenie et al. (2014) identified compound heterozygous mutations in the IGHMBP2 gene: a c.138T-A transversion, resulting in a cys46-to-ter (C46X) substitution, and a 2-bp deletion (c.2911_2912delAG) in the last exon of the gene, resulting in a frameshift and premature termination (Arg971GlufsTer4; 600502.0011). The mutations in the sisters, which were found by whole-exome sequencing, segregated with the disorder in the family; they were not present in the 1000 Genomes Project database or in an in-house exome database of 480 control individuals. Patient cells did not show evidence of nonsense-mediated mRNA decay, and the truncated mutant proteins showed similar cellular localization as controls. Two Serbian sibs with the disorder were found to be compound heterozygous for C46X and a c.604T-G transversion, resulting in a phe202-to-val (F202V; 600502.0012) substitution at a conserved residue in part of an alpha-helix in domain 1A that is not central to the protein structure. Patient fibroblast and lymphoblastoid cells showed decreased protein levels compared to controls, but higher levels than those observed in patients with the more severe phenotype of distal spinal muscular atrophy-1 (DSMA1; 604320). Schottmann et al. (2015) identified compound heterozygosity for the C46X and c.2911_2912delAG mutations in a woman with CMT2S from the United Kingdom. Her sister was reportedly similarly affected. (less)
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Uncertain significance
(-)
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no assertion criteria provided
Method: literature only
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Distal spinal muscular atrophy
Affected status: yes
Allele origin:
germline
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Inherited Neuropathy Consortium
Accession: SCV000929681.1
First in ClinVar: Jul 27, 2019 Last updated: Jul 27, 2019 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001922331.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001963176.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Recessive truncating IGHMBP2 mutations presenting as axonal sensorimotor neuropathy. | Schottmann G | Neurology | 2015 | PMID: 25568292 |
Truncating and missense mutations in IGHMBP2 cause Charcot-Marie Tooth disease type 2. | Cottenie E | American journal of human genetics | 2014 | PMID: 25439726 |
Infantile spinal muscular atrophy with respiratory distress type 1 (SMARD1). | Grohmann K | Annals of neurology | 2003 | PMID: 14681881 |
Text-mined citations for rs372000714 ...
HelpRecord last updated May 01, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.