ClinVar Genomic variation as it relates to human health
NM_024312.5(GNPTAB):c.1196C>T (p.Ser399Phe)
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.1196C>T (p.Ser399Phe)
Variation ID: 38413 Accession: VCV000038413.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q23.2 12: 101770109 (GRCh38) [ NCBI UCSC ] 12: 102163887 (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 1, 2013 Feb 28, 2024 Jan 22, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_024312.5:c.1196C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_077288.2:p.Ser399Phe missense NC_000012.12:g.101770109G>A NC_000012.11:g.102163887G>A NG_021243.1:g.65759C>T Q3T906:p.Ser399Phe - Protein change
- S399F
- Other names
- AY687932:c.1196C>T
- Canonical SPDI
- NC_000012.12:101770108: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
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
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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GNPTAB | - | - |
GRCh38 GRCh37 |
1540 | 1561 |
Conditions - Germline
Condition
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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
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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/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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- | RCV000031967.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 22, 2024 | RCV000820177.13 | |
Pathogenic (1) |
no assertion criteria provided
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Sep 10, 2020 | RCV001831620.8 |
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
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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
(Jan 22, 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: SCV000960877.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 399 of the GNPTAB protein (p.Ser399Phe). … (more)
This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 399 of the GNPTAB protein (p.Ser399Phe). This variant is present in population databases (rs281865026, gnomAD 0.003%). This missense change has been observed in individual(s) with GNPTAB-related conditions (PMID: 16630736, 19659762, 23566849, 27710913). ClinVar contains an entry for this variant (Variation ID: 38413). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GNPTAB protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GNPTAB function (PMID: 24375680, 24550498, 25505245). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Pseudo-Hurler polydystrophy
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
biparental
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Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Accession: SCV004692830.1
First in ClinVar: Feb 28, 2024 Last updated: Feb 28, 2024 |
Sex: male
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Pseudo-Hurler polydystrophy
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Lifecell International Pvt. Ltd
Accession: SCV003926489.1
First in ClinVar: May 27, 2023 Last updated: May 27, 2023 |
Comment:
A Homozygote Missense variant c.1196C>T in Exon 10 of the GNPTAB gene that results in the amino acid substitution p.Ser399Phe was identified. The variant was … (more)
A Homozygote Missense variant c.1196C>T in Exon 10 of the GNPTAB gene that results in the amino acid substitution p.Ser399Phe was identified. The variant was found in ClinVar (Variant ID: 38413) with a classification of Conflicting interpretations of pathogenicity and a review status of (1 star) criteria provided, single submitter. The observed variant has a maximum allele frequency of 0.00002/0.00003% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. The variant has been previously reported by Encarnação M, et al, 2009. Functional analysis showed the mutation leads to overexpression of the enzyme. (Qian Y et al, 2015) Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines. (less)
Ethnicity/Population group: Asian
Geographic origin: India
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Pathogenic
(Sep 10, 2020)
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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: SCV002088593.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
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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: SCV000054659.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2013 |
Comment:
Converted during submission to Pathogenic.
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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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Solving a case of allelic dropout in the GNPTAB gene: implications in the molecular diagnosis of mucolipidosis type III alpha/beta. | Coutinho MF | Journal of pediatric endocrinology & metabolism : JPEM | 2016 | PMID: 27710913 |
Analysis of mucolipidosis II/III GNPTAB missense mutations identifies domains of UDP-GlcNAc:lysosomal enzyme GlcNAc-1-phosphotransferase involved in catalytic function and lysosomal enzyme recognition. | Qian Y | The Journal of biological chemistry | 2015 | PMID: 25505245 |
Mislocalization of phosphotransferase as a cause of mucolipidosis III αβ. | van Meel E | Proceedings of the National Academy of Sciences of the United States of America | 2014 | PMID: 24550498 |
Mucolipidosis II-related mutations inhibit the exit from the endoplasmic reticulum and proteolytic cleavage of GlcNAc-1-phosphotransferase precursor protein (GNPTAB). | De Pace R | Human mutation | 2014 | PMID: 24375680 |
Mucolipidosis II and III alpha/beta in Brazil: analysis of the GNPTAB gene. | Cury GK | Gene | 2013 | PMID: 23566849 |
Mucolipidosis III Alpha/Beta – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY. | Adam MP | - | 2012 | PMID: 20301730 |
Molecular analysis of the GNPTAB and GNPTG genes in 13 patients with mucolipidosis type II or type III - identification of eight novel mutations. | Encarnação M | Clinical genetics | 2009 | PMID: 19659762 |
When Mucolipidosis III meets Mucolipidosis II: GNPTA gene mutations in 24 patients. | Bargal R | Molecular genetics and metabolism | 2006 | PMID: 16630736 |
Text-mined citations for rs281865026 ...
HelpRecord last updated Apr 20, 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.