ClinVar Genomic variation as it relates to human health
NM_001613.4(ACTA2):c.445C>T (p.Arg149Cys)
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_001613.4(ACTA2):c.445C>T (p.Arg149Cys)
Variation ID: 18276 Accession: VCV000018276.57
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q23.31 10: 88941794 (GRCh38) [ NCBI UCSC ] 10: 90701551 (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 Apr 4, 2013 Mar 10, 2024 Oct 18, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001613.4:c.445C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001604.1:p.Arg149Cys missense NM_001141945.3:c.445C>T NP_001135417.1:p.Arg149Cys missense NM_001320855.2:c.445C>T NP_001307784.1:p.Arg149Cys missense NM_001406462.1:c.445C>T NP_001393391.1:p.Arg149Cys missense NM_001406463.1:c.445C>T NP_001393392.1:p.Arg149Cys missense NM_001406464.1:c.445C>T NP_001393393.1:p.Arg149Cys missense NM_001406466.1:c.334C>T NP_001393395.1:p.Arg112Cys missense NM_001406467.1:c.316C>T NP_001393396.1:p.Arg106Cys missense NM_001406468.1:c.316C>T NP_001393397.1:p.Arg106Cys missense NM_001406469.1:c.316C>T NP_001393398.1:p.Arg106Cys missense NM_001406471.1:c.445C>T NP_001393400.1:p.Arg149Cys missense NC_000010.11:g.88941794G>A NC_000010.10:g.90701551G>A NG_011541.1:g.54597C>T LRG_781:g.54597C>T LRG_781t1:c.445C>T LRG_781p1:p.Arg149Cys LRG_781t2:c.445C>T LRG_781p2:p.Arg149Cys P62736:p.Arg149Cys - Protein change
- R149C, R106C, R112C
- Other names
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- Canonical SPDI
- NC_000010.11:88941793: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
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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ACTA2 | Little evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
312 | 577 |
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 (2) |
criteria provided, single submitter
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Oct 18, 2023 | RCV000019938.48 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 16, 2021 | RCV000246692.12 | |
Pathogenic (4) |
criteria provided, single submitter
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Jan 21, 2021 | RCV000505736.13 | |
Pathogenic (1) |
no assertion criteria provided
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Mar 28, 2016 | RCV000581791.9 |
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
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
(Nov 19, 2012)
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criteria provided, single submitter
Method: clinical testing
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Familial thoracic aortic aneurysm and aortic dissection
Affected status: yes
Allele origin:
germline
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Center for Human Genetics, Inc, Center for Human Genetics, Inc
Accession: SCV000693698.1
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
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Pathogenic
(Jan 21, 2021)
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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: SCV000233295.6
First in ClinVar: Jul 05, 2015 Last updated: Sep 23, 2021 |
Comment:
Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 18276; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts … (more)
Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 18276; Landrum et al., 2016); 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: 31911781, 29055370, 24020716, 25644172, 24243736, 21212136, 19778989, 19409525, 19639654, 17994018, 29907982) (less)
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Pathogenic
(Jun 16, 2021)
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criteria provided, single submitter
Method: clinical testing
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Familial thoracic aortic aneurysm and aortic dissection
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000319236.6
First in ClinVar: Oct 02, 2016 Last updated: Nov 29, 2022 |
Comment:
The p.R149C pathogenic mutation (also known as c.445C>T), located in coding exon 4 of the ACTA2 gene, results from a C to T substitution at … (more)
The p.R149C pathogenic mutation (also known as c.445C>T), located in coding exon 4 of the ACTA2 gene, results from a C to T substitution at nucleotide position 445. The arginine at codon 149 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation, which is located in the hydrophobic cleft of alpha-actin, was originally reported in five families in one study. In one large family with thoracic aortic aneurysms and dissections (TAAD), this mutation segregated with TAAD and livedo reticularis. In two additional families, iris flocculi also segregated with the mutation (Guo DC et al. Nat Genet. 2007;39(12):1488-1493). Subsequently, premature coronary artery disease was also reported in one of the families (Guo DC et al. Am J Hum Genet. 2009;84(5):617-627). In another study, this mutation was reported in a patient with an acute thoracoabdominal aortic dissection (Stanford B type), livedo reticularis, and iris cysts. In addition, there was a sibling with an acute aortic dissection (Stanford A type) and iris cysts, and their mother had the same ocular features, but mutation analysis was not performed on the sibling or the mother (Morisaki H et al. Hum Mutat. 2009;30(10):4106-1411). Based on the supporting evidence, p.R149C is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Oct 18, 2023)
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criteria provided, single submitter
Method: clinical testing
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Aortic aneurysm, familial thoracic 6
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000541639.11
First in ClinVar: Oct 11, 2015 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 149 of the ACTA2 protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 149 of the ACTA2 protein (p.Arg149Cys). This variant is present in population databases (rs121434526, gnomAD 0.0008%). This missense change has been observed in individuals with thoracic aortic aneurysms and dissections (PMID: 19409525, 21212136, 21248741, 24020716, 25644172). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 18276). 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 not expected to disrupt ACTA2 protein function. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 28, 2016)
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no assertion criteria provided
Method: clinical testing
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Aortic aneurysm, familial thoracic 2
Affected status: yes
Allele origin:
germline
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Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital
Accession: SCV000692264.1
First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018 |
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Pathogenic
(Jan 05, 2017)
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no assertion criteria provided
Method: provider interpretation
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not provided
Affected status: unknown
Allele origin:
germline
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Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000924713.1
First in ClinVar: Jun 29, 2019 Last updated: Jun 29, 2019 |
Comment:
The patient had genetic testing. The test included sequencing of 10 genes associated with aneurysms and dissections and related conditions: ACTA2, CBS, COL3A1, FBN1, FBN2, … (more)
The patient had genetic testing. The test included sequencing of 10 genes associated with aneurysms and dissections and related conditions: ACTA2, CBS, COL3A1, FBN1, FBN2, MYH11, SLC2A10, SMAD3, TGFBR1 and TGFBR2. Results reported on February 21, 2013 show that a variant was found: p.Arg149Cys (c.445C>T) in the ACTA2 gene The lab classifies this variant as pathogenic. Given significant case and segregation data we consider this variant very likely disease causing and we feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least seven unrelated cases of hereditary thoracic aortic aneurysm and dissection (including this patient's family). There is strong case and segregation data. Guo, et al, 2008 (PMC: 2680995) reported this variant in four pedigrees of patients with aneurysm/dissection, coronary artery disease and livedo reticularis. This is the most common variant in their cohort of patients with ACTA2 variants, 45 out of 134 individuals with ACTA2 variants (33%). Of the 45 individuals from their cohort, 24 had TAAD and 12 had early onset coronary artery disease. Morisaki, et al, 2009 (PMID: 19639654) reported this variant in a proband who had a positive family history of aortic dissection and iris folliculi. She had been an amateur tennis player in her teens. She had an uneventful delivery of a healthy child 4 years prior to referral. At age 31 Y she experienced an acute Stanford type B dissection during spontaneous vaginal delivery of her second child at 40 weeks. She was treated conservatively with antihypertensive therapy and three weeks later she had aggravation of the dissection and underwent and endovascular repair with a tube stent graft. The patient had livedo reticularis on both legs and iris folliculi bilaterally. Her brother had a Stanford type A aortic dissection at 28 Y and iris folliculi but no livedo reticularis. Disabella, et al, 2011 (PMID: 21212136) reported this variant in a family with three affected individuals. One, a 62 Y female with a pre-op AR of 4.8 cm underwent a Tirone-David replacement after having a type A dissection and borderline hypertension. 38 Y female had a pre-op AR of 4.5 cm and A type a dissection during pregnancy at 33 Y and second type b dissection at 35 Y. She had coronary calcification. A 36 Y M had an aortic root of 3.8 cm (z-score: 4.27), a 28 Y male had an aortic root of 4.1 cm (z-score of 4.49 cm). A 7 Y male had an aortic root of 2.04 (z-score: 1.42). Ambry Genetics reports this variant in one of their patients with TAAD. They did not provide phenotypic details. The variant occurs within the hydrophobic cleft between subdomains 1 and 3 and the Cys substitution is expected to impede the actin-ABP interaction as well as actin-actin contacts. of the protein, as does R118 variants which also predispose to early onset CAD. In silico analysis with PolyPhen-2 predicts the variant to be possibly damaging (HumVar: 0.761). The Arg at codon 149 is conserved across species, as are neighboring amino acids, and much of the ACTA2 gene. Another variant has been reported in association with disease at this codon, p.R149L which had multiple affected individuals with aortic disease, premature CAD and premature stroke. There are seven individuals with missense variation at codon 149 listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >125,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. Two individuals have p.R149C and five individuals have p.R149H. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001808589.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001967669.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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Pathogenic
(May 01, 2009)
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no assertion criteria provided
Method: literature only
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AORTIC ANEURYSM, FAMILIAL THORACIC 6
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000040236.4
First in ClinVar: Apr 04, 2013 Last updated: Mar 10, 2024 |
Comment on evidence:
In a large family in which thoracic aortic aneurysm with dissection segregated with reduced penetrance (AAT6; 611788), Guo et al. (2007) found a heterozygous 492C-T … (more)
In a large family in which thoracic aortic aneurysm with dissection segregated with reduced penetrance (AAT6; 611788), Guo et al. (2007) found a heterozygous 492C-T transition in exon 5 of the ACTA2 gene that caused an arg149-to-cys (R149C) amino acid substitution. In further studies, 4 additional families with the ACTA2 mutation were found; however, each family had a unique haplotype, implying that the mutations arose de novo in multiple families. Livedo reticularis and iris flocculi were found together or separately in some of these families. Guo et al. (2009) analyzed 45 individuals with the R149C mutation and found that, in addition to the already established predisposition to TAAD, this mutation led to coronary artery disease (24 mutation carriers with TAAD, 12 with coronary artery disease). (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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Results of next-generation sequencing gene panel diagnostics including copy-number variation analysis in 810 patients suspected of heritable thoracic aortic disorders. | Overwater E | Human mutation | 2018 | PMID: 29907982 |
Gene panel sequencing in heritable thoracic aortic disorders and related entities - results of comprehensive testing in a cohort of 264 patients. | Campens L | Orphanet journal of rare diseases | 2015 | PMID: 25644172 |
Iris Flocculi as an ocular marker of ACTA2 mutation in familial thoracic aortic aneurysms and dissections. | Chamney S | Ophthalmic genetics | 2015 | PMID: 24020716 |
Three novel mutations in the ACTA2 gene in German patients with thoracic aortic aneurysms and dissections. | Hoffjan S | European journal of human genetics : EJHG | 2011 | PMID: 21248741 |
Risk of dissection in thoracic aneurysms associated with mutations of smooth muscle alpha-actin 2 (ACTA2). | Disabella E | Heart (British Cardiac Society) | 2011 | PMID: 21212136 |
Mutation of ACTA2 gene as an important cause of familial and nonfamilial nonsyndromatic thoracic aortic aneurysm and/or dissection (TAAD). | Morisaki H | Human mutation | 2009 | PMID: 19639654 |
Mutations in smooth muscle alpha-actin (ACTA2) cause coronary artery disease, stroke, and Moyamoya disease, along with thoracic aortic disease. | Guo DC | American journal of human genetics | 2009 | PMID: 19409525 |
Mutations in smooth muscle alpha-actin (ACTA2) lead to thoracic aortic aneurysms and dissections. | Guo DC | Nature genetics | 2007 | PMID: 17994018 |
Text-mined citations for rs121434526 ...
HelpRecord last updated Apr 15, 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.