ClinVar Genomic variation as it relates to human health
NM_002180.3(IGHMBP2):c.1488C>A (p.Cys496Ter)
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
-
NM_002180.3(IGHMBP2):c.1488C>A (p.Cys496Ter)
Variation ID: 234316 Accession: VCV000234316.37
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 11q13.3 11: 68933864 (GRCh38) [ NCBI UCSC ] 11: 68701332 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Jul 24, 2016 Feb 28, 2024 Jan 23, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_002180.3:c.1488C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002171.2:p.Cys496Ter nonsense NC_000011.10:g.68933864C>A NC_000011.9:g.68701332C>A NG_007976.1:g.35014C>A LRG_250:g.35014C>A LRG_250t1:c.1488C>A LRG_250p1:p.Cys496Ter - Protein change
- C496*
- Other names
- -
- Canonical SPDI
- NC_000011.10:68933863:C:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
0.00020 (A)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
Trans-Omics for Precision Medicine (TOPMed) 0.00015
The Genome Aggregation Database (gnomAD) 0.00016
1000 Genomes Project 0.00020
1000 Genomes Project 30x 0.00031
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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. |
|||
IGHMBP2 | - | - |
GRCh38 GRCh37 |
1318 | 1397 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
---|---|---|---|---|
Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
|
Oct 27, 2022 | RCV000219401.27 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Sep 2, 2022 | RCV000235082.8 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 23, 2024 | RCV000539394.10 | |
Pathogenic (1) |
criteria provided, single submitter
|
Oct 24, 2018 | RCV000780353.1 | |
Pathogenic (1) |
criteria provided, single submitter
|
- | RCV001172566.1 | |
Pathogenic (1) |
criteria provided, single submitter
|
Jun 14, 2022 | RCV002277579.1 | |
Pathogenic (1) |
criteria provided, single submitter
|
Mar 23, 2020 | RCV002390588.1 |
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
Help
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
Help
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. |
|
---|---|---|---|---|---|
Pathogenic
(Aug 18, 2015)
|
criteria provided, single submitter
Method: research
|
Autosomal recessive distal spinal muscular atrophy 1
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
maternal
|
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine
Accession: SCV000292359.1
First in ClinVar: Jul 24, 2016 Last updated: Jul 24, 2016 |
Comment:
This variant has been previously reported as disease-causing and was identified in trans with a predicted pathogenic variant in an individual with congenital hypotonia.
Number of individuals with the variant: 1
|
|
Pathogenic
(Oct 26, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000336679.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
|
Pathogenic
(May 02, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000604018.2
First in ClinVar: Sep 30, 2017 Last updated: Feb 17, 2019 |
Comment:
The p.Cys496Ter variant has been reported in homozygous form as well as in compound heterozygous form together with missense or other nonsense variants in infants … (more)
The p.Cys496Ter variant has been reported in homozygous form as well as in compound heterozygous form together with missense or other nonsense variants in infants with spinal muscular atrophy with respiratory distress type 1 (SMARD1) with age onset of respiratory distress ranging from 3 - 91 days after birth (Grohmann 2003). Many affected infants presented with intrauterine growth restriction, decreased fetal movements, weak cry, congenital foot deformities due to early involvement of distal muscles of the lower limbs, eventration of the diaphragm due to a diaphragmatic paralysis, involvement of the autonomic nervous system, neurogenic changes in electromyography, decrease in motor nerve conduction velocity and absence of motor response after maximum stimulation, as well as fiber hypertrophy and atrophy on muscle biopsy (Grohmann 2003). Furthermore, Maystad et al. (2004) reported an infant who presented at 2 months with muscular weakness, at 2.5 month with respiratory distress and who died at 6 months. He carried the same p.Cys496Ter variant but a second IGHMBP2 variant was not identified (Maystad 2004). Additionally, Litvinenko et al. (2014) reported two infant siblings with p.Cys496Ter and Gln260fs compound heterozygous variants with severe spinal muscular atrophy respiratory distress 1, persistent eventration of the right hemidiaphragm, hypotonia due to hypo- and areflexia, complete paralysis of the limbs and mild contractures, electromyography showing active denervation, and total absence of IGHMBP2 enzyme activity. Finally, Cottenie et al. (2014) reported a 15 year old male with foot drop (first presenting at age 4), limb weakness, and ankle foot orthoses, who carried p.Cys496Ter and a missense variant. (less)
|
|
Pathogenic
(Oct 24, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Charcot-Marie-Tooth disease, axonal, type 2S
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000917543.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: IGHMBP2 c.1488C>A (p.Cys496X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: IGHMBP2 c.1488C>A (p.Cys496X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00015 in 259950 control chromosomes (gnomAD). The variant, c.1488C>A, has been reported in the literature in one compound heterozygote affected with Charcot-Marie-Tooth disease type 2B2 (CMT2) (Cottenie_2014) and more frequently in compound heterozygotes and homozygotes affected with spinal muscular atrophy with respiratory distress type 1 (SMARD1)( Grohmann_2003). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic for CMT2. (less)
|
|
Pathogenic
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive distal spinal muscular atrophy 1
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001138369.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
|
|
Likely pathogenic
(-)
|
criteria provided, single submitter
Method: research
|
Charcot-Marie-Tooth disease, axonal, type 2S
Spinal muscular atrophy, distal, autosomal recessive, 1
Affected status: no
Allele origin:
germline
|
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill
Study: NSIGHT-NC NEXUS
Accession: SCV001251514.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
The IGHMBP2 c.1488C>A (p.C496*) nonsense variant is predicted to result in an absent or aberrant protein. This variant has been observed in the compound heterozygous … (more)
The IGHMBP2 c.1488C>A (p.C496*) nonsense variant is predicted to result in an absent or aberrant protein. This variant has been observed in the compound heterozygous state in individuals with Charcot-Marie-Tooth disease type 2S or spinal muscular atrophy with respiratory distress type 1 (SMARD1) (PMID: 14506069; 15108294; 19157874; 23449687; 25439726). (less)
Number of individuals with the variant: 1
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Charcot-Marie-Tooth disease
Affected status: yes
Allele origin:
germline
|
Molecular Genetics Laboratory, London Health Sciences Centre
Accession: SCV001335628.1
First in ClinVar: Jun 14, 2020 Last updated: Jun 14, 2020 |
|
|
Pathogenic
(Jun 14, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Neurodevelopmental disorder
Affected status: yes
Allele origin:
germline
|
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes
Accession: SCV002564536.1
First in ClinVar: Aug 29, 2022 Last updated: Aug 29, 2022 |
|
|
Pathogenic
(Mar 23, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002700863.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.C496* pathogenic mutation (also known as c.1488C>A), located in coding exon 10 of the IGHMBP2 gene, results from a C to A substitution at … (more)
The p.C496* pathogenic mutation (also known as c.1488C>A), located in coding exon 10 of the IGHMBP2 gene, results from a C to A substitution at nucleotide position 1488. This changes the amino acid from a cysteine to a stop codon within coding exon 10. This alteration has been detected in the homozygous and compound heterozygous states in patients with spinal muscular atrophy with respiratory distress type 1 (SMARD1) (Grohmann K et al. Ann. Neurol., 2003 Dec;54:719-24; Joseph S et al. Neuromuscul. Disord., 2009 Mar;19:193-5; Pitt M et al. Brain, 2003 Dec;126:2682-92; San Millan B et al. Clin. Neuropathol.;35:58-65). This alteration has also been detected in the compound heterozygous state in a patient with Charcot-Marie-Tooth disease, type 2 (Cottenie E et al. Am. J. Hum. Genet., 2014 Nov;95:590-601). 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)
Number of individuals with the variant: 1
|
|
Pathogenic
(Sep 02, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive distal spinal muscular atrophy 1
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV001245043.3
First in ClinVar: May 04, 2020 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Charcot-Marie-Tooth disease, axonal, type 2S (MIM#616155), and distal hereditary motor neuronopathy, type VI (MIM#604320). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (42 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported many times as pathogenic in individuals with either spinal muscular atrophy with respiratory distress (SMARD) or Charcot-Marie-Tooth (CMT) (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and has been observed in both compound heterozygous and homozygous individuals with SMARD, and rarely in individuals with CMT (ClinVar, PMID: 25439726, PMID: 30598237). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
|
|
Pathogenic
(Oct 27, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000278983.12
First in ClinVar: May 29, 2016 Last updated: Mar 04, 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; This … (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; This variant is associated with the following publications: (PMID: 23449687, 25439726, 15108294, 25525159, 29431110, 26709713, 31827005, 31589614, 33442022, 32573669, 32376792, 14681881, 34726235) (less)
|
|
Pathogenic
(May 16, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002023141.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
Pathogenic
(Jan 23, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
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
|
Invitae
Accession: SCV000642306.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Cys496*) 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.Cys496*) 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 (rs145226920, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with spinal muscular atrophy with respiratory distress 1 (SMARD1) (PMID: 14506069, 14681881, 19157874, 23449687, 26257172). ClinVar contains an entry for this variant (Variation ID: 234316). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001808620.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021 |
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001920518.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001955126.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001971384.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
|
|
click to load more click to collapse |
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 |
---|---|---|---|---|
Spinal muscular atrophy with respiratory distress type 1: A multicenter retrospective study. | Viguier A | Neuromuscular disorders : NMD | 2019 | PMID: 30598237 |
Spinal muscular atrophy with respiratory distress type 1 (SMARD1) Report of a Spanish case with extended clinicopathological follow-up. | San Millan B | Clinical neuropathology | 2016 | PMID: 26709713 |
Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy. | Gonzaga-Jauregui C | Cell reports | 2015 | PMID: 26257172 |
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 |
One novel and one recurrent mutation in IGHMBP2 gene, causing severe spinal muscular atrophy respiratory distress 1 with onset soon after birth. | Litvinenko I | Journal of child neurology | 2014 | PMID: 23449687 |
Interfamilial phenotypic heterogeneity in SMARD1. | Joseph S | Neuromuscular disorders : NMD | 2009 | PMID: 19157874 |
Allelic heterogeneity of SMARD1 at the IGHMBP2 locus. | Maystadt I | Human mutation | 2004 | PMID: 15108294 |
Infantile spinal muscular atrophy with respiratory distress type 1 (SMARD1). | Grohmann K | Annals of neurology | 2003 | PMID: 14681881 |
Severe infantile neuropathy with diaphragmatic weakness and its relationship to SMARD1. | Pitt M | Brain : a journal of neurology | 2003 | PMID: 14506069 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=IGHMBP2 | - | - | - | - |
click to load more click to collapse |
Text-mined citations for rs145226920 ...
HelpRecord last updated Mar 17, 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.