ClinVar Genomic variation as it relates to human health
NM_000404.4(GLB1):c.602G>A (p.Arg201His)
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.602G>A (p.Arg201His)
Variation ID: 198077 Accession: VCV000198077.48
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.3 3: 33058220 (GRCh38) [ NCBI UCSC ] 3: 33099712 (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 Jun 28, 2015 Apr 15, 2024 Mar 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000404.4:c.602G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000395.3:p.Arg201His missense NM_001079811.3:c.512G>A NP_001073279.2:p.Arg171His missense NM_001135602.3:c.341-4671G>A intron variant NM_001317040.1:c.746G>A NM_001317040.2:c.746G>A NP_001303969.2:p.Arg249His missense NM_001393580.1:c.602G>A NP_001380509.1:p.Arg201His missense NC_000003.12:g.33058220C>T NC_000003.11:g.33099712C>T NG_009005.1:g.43983G>A - Protein change
- R201H, R171H, R249H
- Other names
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- Canonical SPDI
- NC_000003.12:33058219:C:T
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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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0.00020 (T)
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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) 0.00005
Trans-Omics for Precision Medicine (TOPMed) 0.00005
The Genome Aggregation Database (gnomAD), exomes 0.00006
Exome Aggregation Consortium (ExAC) 0.00009
1000 Genomes Project 0.00020
1000 Genomes Project 30x 0.00031
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
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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GLB1 | - | - |
GRCh38 GRCh37 |
1038 | 1143 |
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
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 (4) |
criteria provided, multiple submitters, no conflicts
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Mar 1, 2023 | RCV000255006.29 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Sep 19, 2018 | RCV000309607.12 | |
Likely pathogenic (1) |
no assertion criteria provided
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Feb 23, 2017 | RCV000665698.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 11, 2019 | RCV000995553.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 16, 2024 | RCV000818052.6 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Mar 29, 2024 | RCV002286710.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 4, 2022 | RCV002500509.2 |
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
(Oct 27, 2014)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000231531.5
First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 8
Sex: mixed
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Pathogenic
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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GM1 gangliosidosis
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000443184.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
The GLB1 c.602G>A (p.Arg201His) missense variant has been identified in a compound heterozygous state with an additional missense variant in eight individuals with GM1 gangliosidosis … (more)
The GLB1 c.602G>A (p.Arg201His) missense variant has been identified in a compound heterozygous state with an additional missense variant in eight individuals with GM1 gangliosidosis (Kaye et al. 1997; Morrone et al. 2000; Paschke et al. 2001; Caciotti et al. 2005; Santamaria et al. 2006; Hofer et al. 2009; Pierson et al. 2012). The p.Arg201His variant has also been reported in a compound heterozygous state in combination with another missense variant in two individuals with an intermediate phenotype between mucopolysaccharidosis (MPS) type IVB and the adult form of GM1 gangliosidosis (Hofer et al. 2009; Moore et al. 2013) and in a homozygous state in an individual with MPS type IVB (Santamaria et al. 2006). The Arg201 residue is highly conserved across vertebrate species (Pierson et al. 2012), and was shown to segregate with disease in an autosomal recessive inheritance pattern where family data were available (Morrone et al. 2000; Paschke et al. 2001; Pierson et al. 2012). The p.Arg201His variant was absent from 140 controls (Kaye et al. 1997; Paschke et al. 2001) and is reported at a frequency of 0.00011 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies in individual leukocytes and fibroblasts carrying the p.Arg201His variant demonstrated a significant reduction in enzyme activity to between 2% and 2.5% of wildtype (Kaye et al. 1997; Caciotti et al. 2005). Based on the collective evidence, the p.Arg201His variant is classified as pathogenic for GLB1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Sep 19, 2018)
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criteria provided, single submitter
Method: clinical testing
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GM1 gangliosidosis
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000966893.1
First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019 |
Comment:
The p.Arg201His variant in GLB1 has been reported in at least 10 individuals wit h clinical features of GM1 gangliosidosis type II/III or Mucopolysaccharidosis t … (more)
The p.Arg201His variant in GLB1 has been reported in at least 10 individuals wit h clinical features of GM1 gangliosidosis type II/III or Mucopolysaccharidosis t ype IV (Morquio syndrome), all of whom were homozygous or compound heterozygous, and segregated with the disease in 1 affected family member (Kaye 1997, Morrone 2000, Santamaria 2006, Santamaria 2007, Hofer 2009, Pierson 2012). This variant has been reported in ClinVar (Variation ID# 198077) and was absent from large p opulation studies. In vitro functional studies provide some evidence that the p. Arg201His variant may impact protein function (Kaye 1997, Iwasaki 2006, Santamar ia 2007). In summary, this variant meets criteria to be classified as pathogenic for GLB1-related disorders in an autosomal recessive manner based upon case obs ervation, segregation studies, absence from controls and functional evidence. AC MG/AMP Criteria applied: PM3_VeryStrong, PM2, PS3_Moderate, PP1 (less)
Number of individuals with the variant: 1
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Pathogenic
(Jun 11, 2019)
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criteria provided, single submitter
Method: clinical testing
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GM1 gangliosidosis type 2
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV001149788.1
First in ClinVar: Feb 03, 2020 Last updated: Feb 03, 2020 |
Sex: female
Tissue: blood
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Pathogenic
(Jan 12, 2022)
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criteria provided, single submitter
Method: clinical testing
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Infantile GM1 gangliosidosis
Affected status: yes
Allele origin:
paternal
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Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV002577399.1
First in ClinVar: Oct 08, 2022 Last updated: Oct 08, 2022 |
Comment:
PM2, PM3, PM5, PP2, PP3, PP5
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Pathogenic
(Mar 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Infantile GM1 gangliosidosis
GM1 gangliosidosis type 2 GM1 gangliosidosis type 3 Mucopolysaccharidosis, MPS-IV-B
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002811687.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Feb 16, 2022)
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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: SCV000321731.9
First in ClinVar: Oct 09, 2016 Last updated: Mar 04, 2023 |
Comment:
Functional studies found that this variant is associated with significantly reduced enzyme activity (Santamaria et al. 2007; Hofer et al., 2009); In silico analysis, which … (more)
Functional studies found that this variant is associated with significantly reduced enzyme activity (Santamaria et al. 2007; Hofer et al., 2009); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 16617000, 17664528, 9203065, 19472408, 11511921, 25600812, 26108645, 25443580, 28577204, 31980526, 31761138, 33240792, 34258138, 32779865) (less)
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Pathogenic
(Dec 28, 2020)
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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: SCV002024831.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 16, 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: SCV000958646.5
First in ClinVar: Aug 14, 2019 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 201 of the GLB1 protein (p.Arg201His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 201 of the GLB1 protein (p.Arg201His). This variant is present in population databases (rs189115557, gnomAD 0.02%). This missense change has been observed in individuals with GM1 gangliosidosis and Morquio B disease (PMID: 9203065, 11511921, 17309651, 20175788, 23430499). ClinVar contains an entry for this variant (Variation ID: 198077). 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%. Experimental studies have shown that this missense change affects GLB1 function (PMID: 9203065, 11504597, 16617000, 17664528). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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Infantile GM1 gangliosidosis
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004807499.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
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Pathogenic
(Mar 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001500297.17
First in ClinVar: Mar 14, 2021 Last updated: Apr 15, 2024 |
Comment:
GLB1: PM3:Strong, PM1, PM2, PP4, PS3:Supporting
Number of individuals with the variant: 3
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Likely pathogenic
(Feb 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: SCV000789861.2
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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not provided
(-)
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no classification provided
Method: phenotyping only
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GM1 gangliosidosis
Affected status: unknown, yes
Allele origin:
maternal,
unknown,
paternal
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GenomeConnect - GM1
Accession: SCV001338922.3
First in ClinVar: Jun 19, 2020 Last updated: Jan 07, 2023 |
Comment:
Variant identified in multiple registry participants including multiple individuals in one family. Variant classified as Pathogenic and reported on 06-01-2020 by Lab or GTR ID … (more)
Variant identified in multiple registry participants including multiple individuals in one family. Variant classified as Pathogenic and reported on 06-01-2020 by Lab or GTR ID 26957. Variant classified as Pathogenic and reported on 10-06-2011 by lab or GTR ID Emory Genetics. Variant classified as Pathogenic and reported on 10-18-2019 by lab or GTR ID Columbia University Precision Genomics Laboratory. Variant classified as Pathogenic and reported on 10-29-2018 by lab or GTR ID Centogene. Variant classified as Pathogenic and reported, most recently, on 08-23-2017 by lab or GTR ID Prevention Genetics.GenomeConnect - GM1 assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. (less)
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
Abnormality of eye movement (present) , Orofacial cleft (present) , Abnormal oral cavity morphology (present) , Abnormal muscle physiology (present) , Abnormality of the musculature … (more)
Abnormality of eye movement (present) , Orofacial cleft (present) , Abnormal oral cavity morphology (present) , Abnormal muscle physiology (present) , Abnormality of the musculature of the limbs (present) , Cognitive impairment (present) , Abnormality of coordination (present) , Anxiety (present) (less)
Indication for testing: Diagnostic
Age: 0-9 years
Sex: female
Method: Exome Sequencing
Testing laboratory: GeneDx
Date variant was reported to submitter: 2020-06-01
Testing laboratory interpretation: Pathogenic
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Abnormal curvature of the vertebral column (present) , Cognitive impairment (present) , Abnormality of coordination (present)
Age: 0-9 years
Sex: male
Method: Single Gene Sequencing
Testing laboratory: PreventionGenetics,PreventionGenetics
Date variant was reported to submitter: 2017-08-10
Testing laboratory interpretation: Pathogenic
Observation 3:
Number of individuals with the variant: 1
Clinical Features:
Phenotypic abnormality (present)
Age: 0-9 years
Sex: male
Method: Single Gene Sequencing
Testing laboratory: PreventionGenetics,PreventionGenetics
Date variant was reported to submitter: 2017-08-23
Testing laboratory interpretation: Pathogenic
Observation 4:
Number of individuals with the variant: 1
Clinical Features:
Myopia (present) , Feeding difficulties (present) , Abnormal large intestine morphology (present) , Abnormal curvature of the vertebral column (present) , Developmental dysplasia of the … (more)
Myopia (present) , Feeding difficulties (present) , Abnormal large intestine morphology (present) , Abnormal curvature of the vertebral column (present) , Developmental dysplasia of the hip (present) , Pectus carinatum (present) , Abnormal muscle physiology (present) , Abnormality of the musculature of the limbs (present) , Cognitive impairment (present) , Abnormality of coordination (present) , Seizure (present) (less)
Age: 10-19 years
Sex: female
Method: Single Gene Sequencing
Testing laboratory: Eurofins NTD LLC (GA)
Date variant was reported to submitter: 2011-10-06
Testing laboratory interpretation: Pathogenic
Observation 5:
Number of individuals with the variant: 1
Clinical Features:
Asthma (present) , Abnormal curvature of the vertebral column (present) , Joint hypermobility (present) , Developmental dysplasia of the hip (present) , Pectus carinatum (present) … (more)
Asthma (present) , Abnormal curvature of the vertebral column (present) , Joint hypermobility (present) , Developmental dysplasia of the hip (present) , Pectus carinatum (present) , Abnormal muscle physiology (present) , Cognitive impairment (present) , Abnormality of coordination (present) , Hypertonia (present) , Seizure (present) , Abnormality of the amniotic fluid (present) (less)
Age: 10-19 years
Sex: male
Method: Single Gene Sequencing
Testing laboratory: Columbia University Precision Genomics Laboratory
Date variant was reported to submitter: 2019-10-18
Testing laboratory interpretation: Pathogenic
Observation 6:
Number of individuals with the variant: 1
Clinical Features:
Myopia (present) , Abnormal retinal morphology (present) , Abnormal cardiovascular system morphology (present) , Abnormality of the liver (present) , Abnormality of the bladder (present) … (more)
Myopia (present) , Abnormal retinal morphology (present) , Abnormal cardiovascular system morphology (present) , Abnormality of the liver (present) , Abnormality of the bladder (present) , Abnormal renal physiology (present) , Abnormality of urine homeostasis (present) , Abnormal curvature of the vertebral column (present) , Increased susceptibility to fractures (present) , Developmental dysplasia of the hip (present) , Abnormal muscle physiology (present) , Abnormality of the musculature of the limbs (present) , Abnormality of the musculature of the thorax (present) , Cutis laxa (present) , Hypopigmentation of the skin (present) , Cognitive impairment (present) , Abnormality of coordination (present) , Hypertonia (present) , Abnormal aggressive, impulsive or violent behavior (present) , Anxiety (present) (less)
Age: 0-9 years
Sex: female
Method: Gene Panel Sequencing
Testing laboratory: Centogene AG - the Rare Disease Company
Date variant was reported to submitter: 2018-10-29
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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β-Galactosidosis in Patient with Intermediate GM1 and MBD Phenotype. | Moore T | JIMD reports | 2013 | PMID: 23430499 |
Exome sequencing as a diagnostic tool in a case of undiagnosed juvenile-onset GM1-gangliosidosis. | Pierson TM | Neurology | 2012 | PMID: 22675082 |
Chemical chaperone therapy: chaperone effect on mutant enzyme and cellular pathophysiology in β-galactosidase deficiency. | Higaki K | Human mutation | 2011 | PMID: 21520340 |
Phenotype determining alleles in GM1 gangliosidosis patients bearing novel GLB1 mutations. | Hofer D | Clinical genetics | 2010 | PMID: 20175788 |
GM1 gangliosidosis and Morquio B disease: expression analysis of missense mutations affecting the catalytic site of acid beta-galactosidase. | Hofer D | Human mutation | 2009 | PMID: 19472408 |
Expression and characterization of 14 GLB1 mutant alleles found in GM1-gangliosidosis and Morquio B patients. | Santamaria R | Journal of lipid research | 2007 | PMID: 17664528 |
Identification of 14 novel GLB1 mutations, including five deletions, in 19 patients with GM1 gangliosidosis from South America. | Santamaria R | Clinical genetics | 2007 | PMID: 17309651 |
Twenty-one novel mutations in the GLB1 gene identified in a large group of GM1-gangliosidosis and Morquio B patients: possible common origin for the prevalent p.R59H mutation among gypsies. | Santamaria R | Human mutation | 2006 | PMID: 16941474 |
Fibroblast screening for chaperone therapy in beta-galactosidosis. | Iwasaki H | Brain & development | 2006 | PMID: 16617000 |
Elastogenesis in cultured dermal fibroblasts from patients with lysosomal beta-galactosidase, protective protein/cathepsin A and neuraminidase-1 deficiencies. | Tatano Y | The journal of medical investigation : JMI | 2006 | PMID: 16538002 |
Primary and secondary elastin-binding protein defect leads to impaired elastogenesis in fibroblasts from GM1-gangliosidosis patients. | Caciotti A | The American journal of pathology | 2005 | PMID: 16314480 |
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 |
Galactonojirimycin derivatives restore mutant human beta-galactosidase activities expressed in fibroblasts from enzyme-deficient knockout mouse. | Tominaga L | Brain & development | 2001 | PMID: 11504597 |
beta-galactosidase gene mutations affecting the lysosomal enzyme and the elastin-binding protein in GM1-gangliosidosis patients with cardiac involvement. | Morrone A | Human mutation | 2000 | PMID: 10737981 |
beta-Galactosidase gene mutations in patients with slowly progressive GM1 gangliosidosis. | Kaye EM | Journal of child neurology | 1997 | PMID: 9203065 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GLB1 | - | - | - | - |
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Text-mined citations for rs189115557 ...
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.