ClinVar Genomic variation as it relates to human health
NM_000891.3(KCNJ2):c.653G>A (p.Arg218Gln)
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_000891.3(KCNJ2):c.653G>A (p.Arg218Gln)
Variation ID: 67585 Accession: VCV000067585.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q24.3 17: 70175692 (GRCh38) [ NCBI UCSC ] 17: 68171833 (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 Feb 6, 2015 Aug 11, 2024 May 13, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000891.3:c.653G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000882.1:p.Arg218Gln missense NC_000017.11:g.70175692G>A NC_000017.10:g.68171833G>A NG_008798.1:g.11158G>A LRG_328:g.11158G>A LRG_328t1:c.653G>A LRG_328p1:p.Arg218Gln - Protein change
- R218Q
- Other names
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- Canonical SPDI
- NC_000017.11:70175691: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.
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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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KCNJ2 | - | - |
GRCh38 GRCh37 |
580 | 604 |
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
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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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not provided (1) |
no classification provided
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- | RCV000058327.3 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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May 13, 2024 | RCV000157273.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 28, 2023 | RCV000255682.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 3, 2023 | RCV000791452.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 23, 2019 | RCV002362693.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 29, 2021 | RCV002483105.1 |
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
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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
(-)
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criteria provided, single submitter
Method: clinical testing
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Andersen Tawil syndrome
Affected status: yes
Allele origin:
germline
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Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV000987445.1
First in ClinVar: Sep 08, 2019 Last updated: Sep 08, 2019 |
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Pathogenic
(Jul 28, 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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GeneDx
Accession: SCV000321798.10
First in ClinVar: Oct 09, 2016 Last updated: Aug 05, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate this variant exerts a dominant-negative effect on channel function (Bendahhou et … (more)
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate this variant exerts a dominant-negative effect on channel function (Bendahhou et al., 2003; Tristani-Firouzi et al., 2002); 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: 17211524, 32843460, 12909315, 22002906, 12163457, 17221872, 23867365, 11371347, 26109178, 16769944, 16834334, 16419128, 30298493, 23644778, 22581653, 12086641, 31509255, 31737537, 32810216, 32383558, 33094497, 33345742, 35460302, 35456365, 14522976, 22589293, 34919635) (less)
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Pathogenic
(Sep 03, 2023)
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criteria provided, single submitter
Method: clinical testing
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Short QT syndrome type 3
Andersen Tawil syndrome
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: SCV000260176.10
First in ClinVar: Feb 06, 2015 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 218 of the KCNJ2 protein (p.Arg218Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 218 of the KCNJ2 protein (p.Arg218Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Andersen-Tawil syndrome (PMID: 11371347, 12163457, 17211524, 17221872, 22589293, 23644778, 23867365). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 67585). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KCNJ2 protein function. Experimental studies have shown that this missense change affects KCNJ2 function (PMID: 11371347, 12086641, 14522976, 16834334, 22002906). This variant disrupts the p.Arg281 amino acid residue in KCNJ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11371347). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 23, 2019)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002658971.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.R218Q pathogenic mutation (also known as c.653G>A), located in coding exon 1 of the KCNJ2 gene, results from a G to A substitution at … (more)
The p.R218Q pathogenic mutation (also known as c.653G>A), located in coding exon 1 of the KCNJ2 gene, results from a G to A substitution at nucleotide position 653. The arginine at codon 218 is replaced by glutamine, an amino acid with highly similar properties. This variant has been reported in multiple individuals with Andersen-Tawil syndrome (ATS), and has been reported to segregate with ATS in families (Plaster NM et al. Cell, 2001 May;105:511-9; Haruna Y et al. Hum. Mutat., 2007 Feb;28:208; Jagodziska M et al. Ann Noninvasive Electrocardiol, 2016 Mar;21:189-95; Choi BO et al. J. Hum. Genet., 2007 Jan;52:280-3; Choi BO et al. J. Hum. Genet., 2007 Jan;52:280-3). In vitro functional assays have indicated this variant to result in reduced channel current, and dominant negative effect (Tristani-Firouzi M et al. J. Clin. Invest., 2002 Aug;110:381-8; Bendahhou S et al. J. Biol. Chem., 2003 Dec;278:51779-85; Bendahhou S et al. J. Biol. Chem., 2003 Dec;278:51779-85). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(May 13, 2024)
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criteria provided, single submitter
Method: clinical testing
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Andersen Tawil syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV005184761.1
First in ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024 |
Comment:
Variant summary: KCNJ2 c.653G>A (p.Arg218Gln) results in a conservative amino acid change located in the Inward rectifier potassium channel, C-terminal (IPR041647) of the encoded protein … (more)
Variant summary: KCNJ2 c.653G>A (p.Arg218Gln) results in a conservative amino acid change located in the Inward rectifier potassium channel, C-terminal (IPR041647) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 252048 control chromosomes. c.653G>A has been reported in the literature in multiple individuals affected with Andersen-Tawil Syndrome (e.g. Plaster_2001, Tristani-Firouzi_2002, Haruna_2007, Choi_2007). These data indicate that the variant is very likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.652C>T, p.Arg218Trp), supporting the critical relevance of codon 218 to KCNJ2 protein function. Multiple publications report experimental evidence and indicate an impact on protein function (Tristani-Firouzi_2002, Seebohm_2012, Bendahhou_2003). The following publications have been ascertained in the context of this evaluation (PMID: 12796536, 17221872, 11371347, 12163457, 14522976, 22002906, 17211524). ClinVar contains an entry for this variant (Variation ID: 67585). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jun 22, 2017)
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criteria provided, single submitter
Method: clinical testing
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Andersen Tawil syndrome
Affected status: yes
Allele origin:
unknown
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Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues
Accession: SCV000611764.1
First in ClinVar: Apr 16, 2017 Last updated: Apr 16, 2017 |
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Pathogenic
(Sep 29, 2021)
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criteria provided, single submitter
Method: clinical testing
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Andersen Tawil syndrome
Short QT syndrome type 3 Atrial fibrillation, familial, 9
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002785124.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Andersen Tawil syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
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Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Accession: SCV004800833.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Sex: male
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Pathogenic
(Oct 27, 2014)
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no assertion criteria provided
Method: clinical testing
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Andersen Tawil syndrome
Affected status: yes
Allele origin:
germline
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Blueprint Genetics
Accession: SCV000207004.1
First in ClinVar: Feb 06, 2015 Last updated: Feb 06, 2015 |
Number of individuals with the variant: 1
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not provided
(-)
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no classification provided
Method: literature only
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Congenital long QT syndrome
Affected status: unknown
Allele origin:
germline
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Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust
Accession: SCV000089847.3
First in ClinVar: Oct 22, 2013 Last updated: Oct 09, 2016 |
Comment:
This variant has been reported in the following publications (PMID:11371347;PMID:12163457;PMID:17211524;PMID:17221872;PMID:22002906).
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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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[Analysis of clinical phenotypes and KCNJ2 gene mutations in a Chinese pedigree affected with Andersen-Tawil syndrome]. | Sun H | Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics | 2018 | PMID: 30298493 |
Coexistence of Andersen-Tawil Syndrome with Polymorphisms in hERG1 Gene (K897T) and SCN5A Gene (H558R) in One Family. | Jagodzińska M | Annals of noninvasive electrocardiology : the official journal of the International Society for Holter and Noninvasive Electrocardiology, Inc | 2016 | PMID: 26109178 |
Cardiac characteristics and long-term outcome in Andersen-Tawil syndrome patients related to KCNJ2 mutation. | Delannoy E | Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology | 2013 | PMID: 23867365 |
Non dominant-negative KCNJ2 gene mutations leading to Andersen-Tawil syndrome with an isolated cardiac phenotype. | Limberg MM | Basic research in cardiology | 2013 | PMID: 23644778 |
Phenotype variability in patients carrying KCNJ2 mutations. | Kimura H | Circulation. Cardiovascular genetics | 2012 | PMID: 22589293 |
Altered stress stimulation of inward rectifier potassium channels in Andersen-Tawil syndrome. | Seebohm G | FASEB journal : official publication of the Federation of American Societies for Experimental Biology | 2012 | PMID: 22002906 |
Genotype-phenotype correlations of KCNJ2 mutations in Japanese patients with Andersen-Tawil syndrome. | Haruna Y | Human mutation | 2007 | PMID: 17221872 |
Mutations of KCNJ2 gene associated with Andersen-Tawil syndrome in Korean families. | Choi BO | Journal of human genetics | 2007 | PMID: 17211524 |
Andersen-Tawil syndrome: prospective cohort analysis and expansion of the phenotype. | Yoon G | American journal of medical genetics. Part A | 2006 | PMID: 16419128 |
Defective potassium channel Kir2.1 trafficking underlies Andersen-Tawil syndrome. | Bendahhou S | The Journal of biological chemistry | 2003 | PMID: 14522976 |
PIP2 binding residues of Kir2.1 are common targets of mutations causing Andersen syndrome. | Donaldson MR | Neurology | 2003 | PMID: 12796536 |
Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome). | Tristani-Firouzi M | The Journal of clinical investigation | 2002 | PMID: 12163457 |
Alterations in conserved Kir channel-PIP2 interactions underlie channelopathies. | Lopes CM | Neuron | 2002 | PMID: 12086641 |
Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen's syndrome. | Plaster NM | Cell | 2001 | PMID: 11371347 |
- | - | - | - | DOI: 10.1016/s0092-8674(01)00342-7 |
- | - | - | - | DOI: 10.1074/jbc.M310278200 |
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Text-mined citations for rs199473384 ...
HelpRecord last updated Aug 18, 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.