ClinVar Genomic variation as it relates to human health
NM_000404.4(GLB1):c.841C>T (p.His281Tyr)
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_000404.4(GLB1):c.841C>T (p.His281Tyr)
Variation ID: 372371 Accession: VCV000372371.9
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.3 3: 33051956 (GRCh38) [ NCBI UCSC ] 3: 33093448 (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 Jan 9, 2017 Feb 28, 2024 Jan 11, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000404.4:c.841C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000395.3:p.His281Tyr missense NM_001079811.3:c.751C>T NP_001073279.2:p.His251Tyr missense NM_001135602.3:c.448C>T NP_001129074.2:p.His150Tyr missense NM_001317040.2:c.985C>T NP_001303969.2:p.His329Tyr missense NM_001393580.1:c.841C>T NP_001380509.1:p.His281Tyr missense NC_000003.12:g.33051956G>A NC_000003.11:g.33093448G>A NG_009005.1:g.50247C>T - Protein change
- H281Y, H329Y, H150Y, H251Y
- Other names
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- Canonical SPDI
- NC_000003.12:33051955: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.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD) 0.00002
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
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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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GLB1 | - | - |
GRCh38 GRCh37 |
1038 | 1143 |
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
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
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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) |
criteria provided, single submitter
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Dec 3, 2020 | RCV000413217.2 | |
Likely pathogenic (2) |
no assertion criteria provided
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May 23, 2017 | RCV000662341.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 11, 2024 | RCV000805468.5 |
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
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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
(Dec 03, 2020)
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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: SCV000490540.2
First in ClinVar: Jan 09, 2017 Last updated: Jan 09, 2017 |
Comment:
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious … (more)
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21214877, 18546276, 11511921, 22353294, 20409738, 21497194, 15714521, 32779865) (less)
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Pathogenic
(Jan 11, 2024)
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criteria provided, single submitter
Method: clinical testing
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Mucopolysaccharidosis, MPS-IV-B
GM1 gangliosidosis
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: SCV000945425.5
First in ClinVar: Aug 14, 2019 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 281 of the GLB1 protein (p.His281Tyr). … (more)
This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 281 of the GLB1 protein (p.His281Tyr). This variant is present in population databases (rs745386663, gnomAD 0.003%). This missense change has been observed in individual(s) with GLB1-related conditions (PMID: 11511921, 15714521, 18546276, 21214877, 21497194). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 372371). 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 GLB1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(May 23, 2017)
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no assertion criteria provided
Method: clinical testing
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Mucopolysaccharidosis, MPS-IV-B
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000791787.2
First in ClinVar: Aug 05, 2018 Last updated: Dec 23, 2019 |
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not provided
(-)
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no classification provided
Method: phenotyping only
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Mucopolysaccharidosis, MPS-IV-B
Affected status: yes
Allele origin:
unknown
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GenomeConnect, ClinGen
Accession: SCV000784706.1
First in ClinVar: Jul 14, 2018 Last updated: Jul 14, 2018 |
Comment:
GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical … (more)
GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Tall stature (present) , Growth hormone excess (present) , Growth hormone deficiency (present) , Failure to thrive (present) , Short stature (present) , Hemihypertrophy (present) … (more)
Tall stature (present) , Growth hormone excess (present) , Growth hormone deficiency (present) , Failure to thrive (present) , Short stature (present) , Hemihypertrophy (present) , Obesity (present) , Overgrowth (present) , Oral-pharyngeal dysphagia (present) , Abnormality of the skull (present) , Abnormality of the nose (present) , Abnormality of the neck (present) , Abnormality of the mouth (present) , Abnormality of the oral cavity (present) , Abnormality of the hair (present) , Abnormal facial shape (present) , Oral cleft (present) , Abnormality of the chin (present) , Ptosis (present) , Abnormal retinal morphology (present) , Abnormality of the optic nerve (present) , Hypermetropia (present) , Myopia (present) , Abnormality of vision (present) , Abnormality of the lens (present) , Abnormality iris morphology (present) , Abnormality of globe size (present) , Abnormality of eye movement (present) , Vertigo (present) , Hyperacusis (present) , Tinnitus (present) , Hearing impairment (present) , Mixed hearing impairment (present) , Sensorineural hearing loss (present) , Conductive hearing impairment (present) , Aplasia/Hypoplasia of the ear (present) , Seizures (present) , Parkinsonism (present) , Abnormality of movement (present) , Memory impairment (present) , Generalized hypotonia (present) , Hypertonia (present) , Encephalopathy (present) , EEG abnormality (present) , Abnormality of coordination (present) , Cognitive impairment (present) , Cerebral palsy (present) , Morphological abnormality of the central nervous system (present) , Cutis laxa (present) , Hyperextensible skin (present) , Epidermal thickening (present) , Generalized abnormality of skin (present) , Hyperhidrosis (present) , Hypohidrosis (present) , Hypopigmentation of the skin (present) , Hyperpigmentation of the skin (present) , Multiple cafe-au-lait spots (present) , Atrophic scars (present) , Skeletal dysplasia (present) , Pectus excavatum (present) , Pectus carinatum (present) , Hip dysplasia (present) , Abnormality of digit (present) , Increased susceptibility to fractures (present) , Joint hypermobility (present) , Abnormality of the curvature of the vertebral column (present) , Abnormality of limb bone morphology (present) , Abnormality of the musculature of the pelvis (present) , Abnormality of the musculature of the thorax (present) , Abnormality of the musculature of the limbs (present) , EMG abnormality (present) , Abnormality of muscle morphology (present) , Abnormality of muscle physiology (present) , Abnormality of facial musculature (present) , Stroke (present) , Hypercholesterolemia (present) , Hypertension (present) , Abnormality of cardiovascular system morphology (present) , Syncope (present) , Cardiomyopathy (present) , Arterial dissection (present) , Abnormal EKG (present) , Arrhythmia (present) , Dilatation (present) , Abnormality of the upper respiratory tract (present) , Abnormal pattern of respiration (present) , Restrictive ventilatory defect (present) , Respiratory insufficiency (present) , Abnormality of the diaphragm (present) , Decreased pulmonary function (present) , Abnormality of the lung (present) , Asthma (present) , Abnormality of the anus (present) , Abnormality of the large intestine (present) , Abnormality of the intestine (present) , Gastrointestinal dysmotility (present) , Abnormality of the liver (present) , Abnormality of the pancreas (present) , Abnormality of the stomach (present) , Abnormality of esophagus morphology (present) , Feeding difficulties (present) , Abnormality of urine homeostasis (present) , Abnormality of the ureter (present) , Abnormality of the urethra (present) , Abnormality of the male genitalia (present) , Abnormality of reproductive system physiology (present) , Abnormality of the female genitalia (present) , Abnormal renal morphology (present) , Abnormal renal physiology (present) , Abnormal sex determination (present) , Abnormality of the bladder (present) , Rheumatoid arthritis (present) , Recurrent infections (present) , Abnormal inflammatory response (present) , Immunodeficiency (present) , Autoimmunity (present) (less)
Indication for testing: Diagnostic, Mucopolysaccharidosis type 4B
Age: 0-9 years
Sex: male
Testing laboratory: Centogene AG - the Rare Disease Company
Date variant was reported to submitter: 2017-10-19
Testing laboratory interpretation: 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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Crystal structure of human β-galactosidase: structural basis of Gm1 gangliosidosis and morquio B diseases. | Ohto U | The Journal of biological chemistry | 2012 | PMID: 22128166 |
Lysosomal multienzymatic complex-related diseases: a genetic study among Portuguese patients. | Coutinho MF | Clinical genetics | 2012 | PMID: 21214877 |
GM1 gangliosidosis and Morquio B disease: an update on genetic alterations and clinical findings. | Caciotti A | Biochimica et biophysica acta | 2011 | PMID: 21497194 |
Novel beta-galactosidase gene mutation p.W273R in a woman with mucopolysaccharidosis type IVB (Morquio B) and lack of response to in vitro chaperone treatment of her skin fibroblasts. | Gucev ZS | American journal of medical genetics. Part A | 2008 | PMID: 18546276 |
Role of beta-galactosidase and elastin binding protein in lysosomal and nonlysosomal complexes of patients with GM1-gangliosidosis. | Caciotti A | Human mutation | 2005 | PMID: 15714521 |
Mutation analyses in 17 patients with deficiency in acid beta-galactosidase: three novel point mutations and high correlation of mutation W273L with Morquio disease type B. | Paschke E | Human genetics | 2001 | PMID: 11511921 |
Text-mined citations for rs745386663 ...
HelpRecord last updated Mar 05, 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.