ClinVar Genomic variation as it relates to human health
NM_024312.5(GNPTAB):c.3613C>T (p.Arg1205Ter)
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_024312.5(GNPTAB):c.3613C>T (p.Arg1205Ter)
Variation ID: 38429 Accession: VCV000038429.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q23.2 12: 101749181 (GRCh38) [ NCBI UCSC ] 12: 102142959 (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 Apr 4, 2013 Feb 28, 2024 Jan 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_024312.5:c.3613C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_077288.2:p.Arg1205Ter nonsense NC_000012.12:g.101749181G>A NC_000012.11:g.102142959G>A NG_021243.1:g.86687C>T - Protein change
- R1205*
- Other names
- AY687932:c.3613C>T
- Canonical SPDI
- NC_000012.12:101749180:G: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
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00001
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 | ||
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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
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. |
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GNPTAB | - | - |
GRCh38 GRCh37 |
1551 | 1572 |
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. |
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Pathogenic (1) |
no assertion criteria provided
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May 10, 2012 | RCV000031986.3 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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May 9, 2022 | RCV000032344.10 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 29, 2024 | RCV000670953.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 9, 2019 | RCV001193437.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 16, 2023 | RCV003488353.2 |
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
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. |
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Pathogenic
(Sep 09, 2019)
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criteria provided, single submitter
Method: clinical testing
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Mucolipidosis
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001362262.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: GNPTAB c.3613C>T (p.Arg1205X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: GNPTAB c.3613C>T (p.Arg1205X) 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 was absent in 251276 control chromosomes (gnomAD) but has been reported in the literature in multiple individuals (both homozygous and compound heterozygous states) affected with Mucolipidosis (Bargal_2006, Kudo_2006, Liu_2016, Tappino_2009). These data indicate that the variant is very likely to be associated with disease. Kudo_2006 measured enzymatic activity in fibroblasts derived from a patient homozygous for this mutation and found to be 4.4% of the activity in normal fibroblasts. A ClinVar submission (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(May 09, 2022)
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criteria provided, single submitter
Method: clinical testing
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Mucolipidosis type II
Affected status: yes
Allele origin:
germline
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Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Accession: SCV002507167.1
First in ClinVar: May 12, 2022 Last updated: May 12, 2022 |
Sex: female
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Pathogenic
(Jan 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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Pseudo-Hurler polydystrophy
Mucolipidosis type II
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: SCV002235705.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg1205*) in the GNPTAB gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg1205*) in the GNPTAB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GNPTAB are known to be pathogenic (PMID: 19617216, 25107912). This variant is present in population databases (rs35333334, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with clinical features of mucolipidosis type II (PMID: 16200072). ClinVar contains an entry for this variant (Variation ID: 38429). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 21, 2017)
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criteria provided, single submitter
Method: clinical testing
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Mucolipidosis type II
Pseudo-Hurler polydystrophy
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000795880.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Mucolipidosis type II
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV002073351.1
First in ClinVar: Feb 04, 2022 Last updated: Feb 04, 2022 |
Comment:
The stop gained p.R1205* in GNPTAB (NM_024312.5) has been previously reported in affected individuals with mucolipidosis (Tappino B et al; Liu S et al). Functional … (more)
The stop gained p.R1205* in GNPTAB (NM_024312.5) has been previously reported in affected individuals with mucolipidosis (Tappino B et al; Liu S et al). Functional studies on skin fibroblasts have revealed a damaging effect (Kudo M et al).The variant has been submitted to ClinVar as Pathogenic. The p.R1205* variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Global developmental delay (present) , Abnormal facial shape (present) , Short stature (present) , Failure to thrive (present) , Posterior plagiocephaly (present) , Coarse facial … (more)
Global developmental delay (present) , Abnormal facial shape (present) , Short stature (present) , Failure to thrive (present) , Posterior plagiocephaly (present) , Coarse facial features (present) , Thick eyebrow (present) , Low-set ears (present) , Large earlobe (present) , Hirsutism (present) , Mandibular prognathia (present) , Limb undergrowth (present) , Bullet-shaped toe phalanx (present) , Distal widening of metacarpals (present) , Skeletal dysplasia (present) (less)
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Pathogenic
(Feb 16, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV004236054.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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pathologic
(May 10, 2012)
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no assertion criteria provided
Method: curation
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Mucolipidosis III Alpha/Beta
Affected status: not provided
Allele origin:
not provided
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GeneReviews
Accession: SCV000054687.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2013 |
Comment:
Converted during submission to Pathogenic.
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Pathogenic
(May 27, 2021)
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no assertion criteria provided
Method: clinical testing
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Mucolipidosis type II
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002088560.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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not provided
(-)
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no classification provided
Method: literature only
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Mucolipidosis type II
Affected status: not provided
Allele origin:
unknown
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GeneReviews
Accession: SCV000055991.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
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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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GNPTAB-Related Disorders. | Adam MP | - | 2019 | PMID: 20301728 |
Mutation Analysis of 16 Mucolipidosis II and III Alpha/Beta Chinese Children Revealed Genotype-Phenotype Correlations. | Liu S | PloS one | 2016 | PMID: 27662472 |
A novel mouse model of a patient mucolipidosis II mutation recapitulates disease pathology. | Paton L | The Journal of biological chemistry | 2014 | PMID: 25107912 |
Mucolipidosis III Alpha/Beta – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY. | Adam MP | - | 2012 | PMID: 20301730 |
Phenotype and genotype in mucolipidoses II and III alpha/beta: a study of 61 probands. | Cathey SS | Journal of medical genetics | 2010 | PMID: 19617216 |
Molecular characterization of 22 novel UDP-N-acetylglucosamine-1-phosphate transferase alpha- and beta-subunit (GNPTAB) gene mutations causing mucolipidosis types IIalpha/beta and IIIalpha/beta in 46 patients. | Tappino B | Human mutation | 2009 | PMID: 19634183 |
When Mucolipidosis III meets Mucolipidosis II: GNPTA gene mutations in 24 patients. | Bargal R | Molecular genetics and metabolism | 2006 | PMID: 16630736 |
Mucolipidosis II (I-cell disease) and mucolipidosis IIIA (classical pseudo-hurler polydystrophy) are caused by mutations in the GlcNAc-phosphotransferase alpha / beta -subunits precursor gene. | Kudo M | American journal of human genetics | 2006 | PMID: 16465621 |
Mucolipidosis II is caused by mutations in GNPTA encoding the alpha/beta GlcNAc-1-phosphotransferase. | Tiede S | Nature medicine | 2005 | PMID: 16200072 |
Text-mined citations for rs35333334 ...
HelpRecord last updated Apr 06, 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.