ClinVar Genomic variation as it relates to human health
NM_000132.4(F8):c.1094A>G (p.Tyr365Cys)
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_000132.4(F8):c.1094A>G (p.Tyr365Cys)
Variation ID: 618104 Accession: VCV000618104.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq28 X: 154966603 (GRCh38) [ NCBI UCSC ] X: 154194878 (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 18, 2019 Feb 20, 2024 Feb 2, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000132.4:c.1094A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000123.1:p.Tyr365Cys missense NC_000023.11:g.154966603T>C NC_000023.10:g.154194878T>C NG_011403.2:g.61121A>G LRG_555:g.61121A>G LRG_555t1:c.1094A>G LRG_555p1:p.Tyr365Cys - Protein change
- Y365C
- Other names
- NM_000132.3(F8):c.1094A>G
- Canonical SPDI
- NC_000023.11:154966602:T:C
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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.
Exome Aggregation Consortium (ExAC) 0.00007
The Genome Aggregation Database (gnomAD) 0.00007
The Genome Aggregation Database (gnomAD), exomes 0.00007
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00009
Trans-Omics for Precision Medicine (TOPMed) 0.00014
- Links
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
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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F8 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
902 | 1172 |
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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Pathogenic (1) |
criteria provided, single submitter
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Feb 1, 2019 | RCV000851582.1 | |
Pathogenic (4) |
reviewed by expert panel
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Feb 2, 2024 | RCV001093532.19 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 24, 2023 | RCV003103835.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 7, 2023 | RCV003489854.1 |
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
(Feb 02, 2024)
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reviewed by expert panel
Method: curation
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Hereditary factor VIII deficiency disease
(X-linked inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen
Accession: SCV004363676.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
The NM_000132.3(F8):c.1094A>G variant predicts a missense change, Tyr365Cys, in the a1 interdomain of FVIII protein, reported to impair activation and deactivation of the protein meeting … (more)
The NM_000132.3(F8):c.1094A>G variant predicts a missense change, Tyr365Cys, in the a1 interdomain of FVIII protein, reported to impair activation and deactivation of the protein meeting PM1 criteria (PMID: 12139751). This variant does not meet the rarity population criteria. It is reported in multiple individuals (>32) in the literature (PMID: 29296726, PMID: 12139751, PMID: 21645180, PMID: 17445092, PMID: 21751985, PMID: 18691168, PMID: 18034822, PMID: 19456877, PMID: 15810915, PMID: 11857744). Of note, this variant is associated with discrepant factor VIII activity levels between the one-stage and two-stage, or chromogenic, assay, and individuals with factor VIII levels measured on a two-stage assay may be within the normal range (EAHAD/CDC Champs databases). Additionally, individuals with this variant may have a mild to no bleeding history. The variant has a REVEL score of 0.756 (threshold >0.6) meeting PP3 criteria. In summary, the variant meets criteria to be classified as pathogenic causing decreased factor VIII activity levels, but may have a lower penetrant bleeding phenotype. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Expert Panel for F8: PS4_Very Strong, PM1, PP4_Moderate, PP3. (less)
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Pathogenic
(Feb 01, 2019)
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criteria provided, single submitter
Method: research
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Hereditary factor IX deficiency disease
Affected status: yes
Allele origin:
unknown
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NIHR Bioresource Rare Diseases, University of Cambridge
Study: ThromboGenomics
Accession: SCV000899296.1 First in ClinVar: Sep 29, 2019 Last updated: Sep 29, 2019 |
Observation 1:
Sex: male
Ethnicity/Population group: European
Observation 2:
Sex: male
Ethnicity/Population group: European
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Likely benign
(Jan 28, 2020)
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criteria provided, single submitter
Method: clinical testing
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Hereditary factor VIII deficiency disease
Affected status: no
Allele origin:
germline
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Versiti Diagnostic Laboratories, Versiti, Inc
Accession: SCV001250580.1
First in ClinVar: May 12, 2020 Last updated: May 12, 2020 |
Comment:
The missense variant F8 c.1094A>G, p.Tyr365Cys (p.Y365C; legacy p.Y346C) in exon 8 changes amino acid tyrosine at codon 365 to cysteine (also described as Y346C). … (more)
The missense variant F8 c.1094A>G, p.Tyr365Cys (p.Y365C; legacy p.Y346C) in exon 8 changes amino acid tyrosine at codon 365 to cysteine (also described as Y346C). The tyrosine at this residue is not well conserved among species. This amino acid change occurs in the a1 interdomain region which plays an important role in activation and degradation of FVIII (Mumford, 2002). Pathogenic variants in F8 are associated with X-linked hemophilia A characterized by mild to severe bleeding due to a quantitative or qualitative deficiency in factor VIII. This variant has been previously described in individuals reported to have hemophilia A, most often mild (Cutler, 2002; Green, 2008; Repesse, 2007); however, it has also been reported in individuals that presented with prolonged APTT without a clinically significant bleeding disorder or with bleeding diathesis that was less severe than expected in individuals or carriers of mild hemophilia A (Mumford, 2002; Lyall, 2008; Kentsis, 2009; Bowyer 2011) and/or individuals who were found to have reduced one-stage FVIII:C values but normal two-stage FVIII:C or FVIII:Ag values (Mumford, 2002; Lyall, 2008; Hill, 2005; Bowyer 2011). The minor allele frequency in the general population is 0.00006645 with an elevated allele frequency of 0.0001388 in the European population and 1 observation in a hemizygous state (gnomAD), which is more frequent than expected for hemophilia A. No functional data is available for this variant. Studies of FVIII protein purified from patient plasma showed decreased activation to FVIIIa at low thrombin concentrations (<1nmol/l) and increased decay of FVIIIa in a molar excess of thrombin (25nmol/l) (Mumford, 2002); the one-stage assay would be most sensitive to this due to the minimal time allowed between thrombin activation and clotting . Multiple lines of in silico computational evidence (Condel, Polyphen2, Mutation Taster, SIFT) predict the variant to be damaging; however, the accuracy of these tools is unknown. In summary, although individuals who are heterozygous or hemizygous for this variant may exhibit reduced FVIII activity levels by one-stage assays, this variant does not appear to result in increased risk for bleeding; therefore, the collective evidence supports F8 c.1094A>G, p.Tyr365Cys as a likely benign variant with respect to hemophilia A. (less)
Number of individuals with the variant: 4
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Uncertain significance
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Hereditary factor VIII deficiency disease
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001331109.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Hereditary factor VIII deficiency disease
Affected status: yes
Allele origin:
unknown
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ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology
Accession: SCV002500865.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022
Comment:
GoldVariant submitter: Dr Karyn Mégy NIHR Bioresource - Cambridge University, UK
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Observation 1: Observation 2: |
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Uncertain significance
(Dec 07, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004241889.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
Comment:
Variant summary: F8 c.1094A>G (p.Tyr365Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: F8 c.1094A>G (p.Tyr365Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.5e-05 in 183378 control chromosomes with a total of 6 hemizygotes, predominantly at a frequency of 0.00015 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in F8 causing Factor VIII Deficiency (Hemophilia A) (6.5e-05 vs 0.0098), allowing no conclusion about variant significance. c.1094A>G has been reported in the literature in multiple individuals affected with mild Factor VIII Deficiency (Hemophilia A), individuals with prolonged PTT and reduced factor VIII activity but minimal or absent bleeding symptoms, individuals with unspecified conditions of coagulation (examples, Bowyer_2011, Cutler_2002, Downes_2019, Hill_2005, Kentsis_2009, SilvaPinto_2012). Most often, those individuals were reported to have reduced one-stage FVIII:C values but normal two-stage FVIII:C or FVIII:Ag values (Bowyer_2011, Hill_2005). These report(s) do not provide unequivocal conclusions about association of the variant with Factor VIII Deficiency (Hemophilia A). Co-occurrences with other pathogenic variant(s) have been reported in an individual with severe Hemophilia A (F8 c.3870delA, p.Glu1292Argfs*16) and the carrier mom was unaffected, providing supporting evidence for a benign role (Kentsis_2009). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 21751985, 11857744, 31064749, 15810915, 19456877, 21645180). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (Pathogenic, n=2, VUS, n=1, Likely benign, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Pathogenic
(Apr 24, 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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000883832.5
First in ClinVar: Feb 18, 2019 Last updated: Feb 20, 2024 |
Comment:
The F8 c.1094A>G; p.Tyr365Cys variant (rs375241473), also known as Tyr346Cys, is published in the medical literature and in gene-specific databases in several individuals with mild … (more)
The F8 c.1094A>G; p.Tyr365Cys variant (rs375241473), also known as Tyr346Cys, is published in the medical literature and in gene-specific databases in several individuals with mild hemophilia (see link to FVIII database, Bowyer 2011, Cutler 2002, Hill 2005). This variant is found in the Genome Aggregation Database in the non-Finnish European populationwith an allele frequency of 0.015% (12/81864 alleles, including 6 hemizygotes). The tyrosine at this position is conserved across species and computational algorithms (PolyPhen2, SIFT) predict this variant is deleterious. Considering available information, this variant is considered pathogenic. References: Link to F8 database: http://f8-db.eahad.org/ Bowyer AE et al. p.Tyr365Cys change in factor VIII: haemophilia A, but not as we know it. Br J Haematol. 2011 Sep;154(5):618-25. Cutler JA et al. The identification and classification of 41 novel mutations in the factor VIII gene (F8C). Hum Mutat. 2002 Mar;19(3):274-8. Hill M et al. Mutation analysis in 51 patients with haemophilia A: report of 10 novel mutations and correlations between genotype and clinical phenotype. Haemophilia. 2005 Mar;11(2):133-41. (less)
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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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GoldVariants, a resource for sharing rare genetic variants detected in bleeding, thrombotic, and platelet disorders: Communication from the ISTH SSC Subcommittee on Genomics in Thrombosis and Hemostasis. | Megy K | Journal of thrombosis and haemostasis : JTH | 2021 | PMID: 34355501 |
Diagnostic high-throughput sequencing of 2396 patients with bleeding, thrombotic, and platelet disorders. | Downes K | Blood | 2019 | PMID: 31064749 |
Specific and global coagulation assays in the diagnosis of discrepant mild hemophilia A. | Bowyer AE | Haematologica | 2013 | PMID: 23812942 |
Molecular diagnosis of haemophilia A at Centro Hospitalar de Coimbra in Portugal: study of 103 families--15 new mutations. | Silva Pinto C | Haemophilia : the official journal of the World Federation of Hemophilia | 2012 | PMID: 21645180 |
Surgery and inhibitor development in hemophilia A: a systematic review. | Eckhardt CL | Journal of thrombosis and haemostasis : JTH | 2011 | PMID: 21838755 |
p.Tyr365Cys change in factor VIII: haemophilia A, but not as we know it. | Bowyer AE | British journal of haematology | 2011 | PMID: 21751985 |
Discordant haemophilia A in male siblings due to a de novo mutation on a familial missense mutant allele. | Kentsis A | Haemophilia : the official journal of the World Federation of Hemophilia | 2009 | PMID: 19456877 |
Haemophilia A mutations in the UK: results of screening one-third of the population. | Green PM | British journal of haematology | 2008 | PMID: 18691168 |
Tyr346-->Cys mutation results in factor VIII:C assay discrepancy and a normal bleeding phenotype - is this mild haemophilia A? | Lyall H | Haemophilia : the official journal of the World Federation of Hemophilia | 2008 | PMID: 18034822 |
Factor VIII (FVIII) gene mutations in 120 patients with hemophilia A: detection of 26 novel mutations and correlation with FVIII inhibitor development. | Repessé Y | Journal of thrombosis and haemostasis : JTH | 2007 | PMID: 17445092 |
Mutation analysis in 51 patients with haemophilia A: report of 10 novel mutations and correlations between genotype and clinical phenotype. | Hill M | Haemophilia : the official journal of the World Federation of Hemophilia | 2005 | PMID: 15810915 |
A Tyr346-->Cys substitution in the interdomain acidic region a1 of factor VIII in an individual with factor VIII:C assay discrepancy. | Mumford AD | British journal of haematology | 2002 | PMID: 12139751 |
The identification and classification of 41 novel mutations in the factor VIII gene (F8C). | Cutler JA | Human mutation | 2002 | PMID: 11857744 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/97530a61-603a-4523-afe2-1c7c833609ed | - | - | - | - |
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Text-mined citations for rs375241473 ...
HelpRecord last updated May 08, 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.