ClinVar Genomic variation as it relates to human health
NM_003560.4(PLA2G6):c.2221C>T (p.Arg741Trp)
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_003560.4(PLA2G6):c.2221C>T (p.Arg741Trp)
Variation ID: 265448 Accession: VCV000265448.10
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 22q13.1 22: 38112559 (GRCh38) [ NCBI UCSC ] 22: 38508566 (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 Oct 10, 2016 Feb 14, 2024 Dec 9, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003560.4:c.2221C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003551.2:p.Arg741Trp missense NM_001004426.3:c.2059C>T NP_001004426.1:p.Arg687Trp missense NM_001199562.3:c.2059C>T NP_001186491.1:p.Arg687Trp missense NM_001349864.2:c.2221C>T NP_001336793.1:p.Arg741Trp missense NM_001349865.2:c.2059C>T NP_001336794.1:p.Arg687Trp missense NM_001349866.2:c.2059C>T NP_001336795.1:p.Arg687Trp missense NM_001349867.2:c.1687C>T NP_001336796.1:p.Arg563Trp missense NM_001349868.2:c.1543C>T NP_001336797.1:p.Arg515Trp missense NM_001349869.2:c.1525C>T NP_001336798.1:p.Arg509Trp missense NC_000022.11:g.38112559G>A NC_000022.10:g.38508566G>A NG_007094.3:g.107220C>T NG_033059.2:g.3111C>T LRG_1015:g.107220C>T LRG_1015t1:c.2221C>T LRG_1015p1:p.Arg741Trp - Protein change
- R741W, R509W, R515W, R687W, R563W
- Other names
- NM_003560.4(PLA2G6):c.2221C>T
- p.Arg741Trp
- Canonical SPDI
- NC_000022.11:38112558: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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0.00020 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD) 0.00004
Exome Aggregation Consortium (ExAC) 0.00006
1000 Genomes Project 0.00020
1000 Genomes Project 30x 0.00031
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
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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PLA2G6 | - | - |
GRCh38 GRCh37 |
1041 | 1072 |
Conditions - Germline
Condition
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
criteria provided, single submitter
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Jul 27, 2016 | RCV000255821.1 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 9, 2023 | RCV000853336.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 2, 2022 | RCV002282096.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 3, 2022 | RCV002494803.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 24, 2023 | RCV002521855.2 | |
Pathogenic (1) |
criteria provided, single submitter
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May 21, 2020 | RCV002470830.1 |
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
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
(Jul 27, 2016)
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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: SCV000322368.6
First in ClinVar: Oct 10, 2016 Last updated: Oct 10, 2016 |
Comment:
The R741W variant in the PLA2G6 gene has been reported previously in association with INAD when present in the homozygous state or when present with … (more)
The R741W variant in the PLA2G6 gene has been reported previously in association with INAD when present in the homozygous state or when present with another missense variant in PLA2G6 (Morgan et al, 2006; Romani et al 2015). The R741W variant was not observed in approximately 6300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R741W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. In vitro enzyme assays demonstrated that the R741W amino acid substitution reduced PLA2G6 enzyme activity (Engel et al., 2010). We interpret R741W as a pathogenic variant. (less)
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Pathogenic
(Sep 24, 2018)
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criteria provided, single submitter
Method: clinical testing
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Dystrophy, Infantile Neuroaxonal
Affected status: yes
Allele origin:
germline
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Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV000996196.1
First in ClinVar: Oct 20, 2019 Last updated: Oct 20, 2019 |
Comment:
This variant has been previously reported as a compound heterozygous or homozygous change inindividuals with Infantile Neuroaxonal Dystrophy (PMID: 20886109, 25164370, 16783378). In vitro enzyme … (more)
This variant has been previously reported as a compound heterozygous or homozygous change inindividuals with Infantile Neuroaxonal Dystrophy (PMID: 20886109, 25164370, 16783378). In vitro enzyme assays demonstrated that the p.Arg741Trp amino acid substitution reduced PLA2G6 enzyme activity (PMID: 20886109). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0007% (1/148108), and thus is presumed to be rare. The c.2221C>T (p.Arg741Trp) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.2221C>T (p.Arg741Trp) variant is classified as Pathogenic. (less)
Number of individuals with the variant: 1
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Pathogenic
(Aug 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Neurodegeneration with brain iron accumulation
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002572188.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
Variant summary: PLA2G6 c.2221C>T (p.Arg741Trp) 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: PLA2G6 c.2221C>T (p.Arg741Trp) 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-06 in 154678 control chromosomes (gnomAD). c.2221C>T has been reported in the literature in homozygous and compound heterozygous individuals affected with infantile neuroaxonal dystrophy (INAD) (e.g. Morgan_2006, Romani_2015, Davids_2016, Darling_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, and it found that the variant protein had 10-25% the activity of wild-type PLA2GA (Engel_2010). Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(May 21, 2020)
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criteria provided, single submitter
Method: clinical testing
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Neurodegeneration with brain iron accumulation 2B
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002767948.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
A heterozygous missense variant, NM_003560.2(PLA2G6):c.2221C>T, has been identified in exon 16 of 17 of the PLA2G6 gene. The variant is predicted to result in a … (more)
A heterozygous missense variant, NM_003560.2(PLA2G6):c.2221C>T, has been identified in exon 16 of 17 of the PLA2G6 gene. The variant is predicted to result in a major amino acid change from arginine to tryptophan at position 741 of the protein (NP_003551.2(PLA2G6):p.(Arg741Trp)). The arginine residue at this position has moderate conservation (100 vertebrates, UCSC), and it is located in a missense hotspot region (Paisan-Ruiz, C. et al. (2009)). In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.0006% (1 heterozygote, 0 homozygotes). The variant has been previously described as pathogenic in multiple patients with infantile neuroaxonal dystrophy (ClinVar, Morgan, NV. et al. (2006), Romani, M. et al. (2015), Kapoor, S. et al. (2016), Al-Maawali, A. et al. (2016), Davids, M. et al. (2016)). Additionally, functional studies have shown that p.R741W leads to an inactive enzyme due to its location at the dimerization interface and also the variant causes loss of enzyme activity (Engel, LA. et al. (2010), Malley, KR. et al. (2018)). A different variant in the same codon resulting in a change to glutamine has also been shown to cause infantile neuroaxonal dystrophy (ClinVar, Paisan-Ruiz, C. et al. (2009)). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. (less)
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Pathogenic
(Mar 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Infantile neuroaxonal dystrophy
Neurodegeneration with brain iron accumulation 2B Autosomal recessive Parkinson disease 14
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002790212.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Likely pathogenic
(Jan 24, 2023)
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criteria provided, single submitter
Method: curation
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PLA2G6-associated neurodegeneration
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV003761467.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
The p.Arg741Trp variant in PLA2G6 has been reported in at least 10 individuals with PLA2G6-associated neurodegeneration (PMID: 16783378, 26668131, 31516627, 30340910, 32860008, 35122944, 25164370, 27196560, … (more)
The p.Arg741Trp variant in PLA2G6 has been reported in at least 10 individuals with PLA2G6-associated neurodegeneration (PMID: 16783378, 26668131, 31516627, 30340910, 32860008, 35122944, 25164370, 27196560, 30713958), segregated with disease in 1 affected relative from 1 family (PMID: 30713958), and has been identified in 0.004% (1/25224) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs530348521). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 265448) and has been interpreted as pathogenic by GeneDx and Rady Children's Institute for Genomic Medicine (Rady Children's Hospital San Diego). Of the 10 affected individuals, 2 of those were homozygotes, which increases the likelihood that the p.Arg741Trp variant is pathogenic (PMID: 25164370, 27196560, 30713958). In vitro functional studies provide some evidence that the p.Arg741Trp variant may impact protein function (PMID: 20886109, 26668131, 35122944). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive PLA2G6-associated neurodegeneration. ACMG/AMP Criteria applied: PM3, PS3_moderate, PP3, PM2_supporting (Richards 2015). (less)
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Pathogenic
(Dec 09, 2023)
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criteria provided, single submitter
Method: clinical testing
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Infantile neuroaxonal dystrophy
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002155675.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 741 of the PLA2G6 protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 741 of the PLA2G6 protein (p.Arg741Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with clinical features of infantile neuroaxonal dystrophy (PMID: 16783378, 25164370, 31516627). ClinVar contains an entry for this variant (Variation ID: 265448). 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 PLA2G6 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PLA2G6 function (PMID: 20886109). This variant disrupts the p.Arg741 amino acid residue in PLA2G6. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18570303, 20669327, 26196026, 26668131, 27268037). 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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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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Vitamin E prevents lipid peroxidation and iron accumulation in PLA2G6-Associated Neurodegeneration. | Villalón-García I | Neurobiology of disease | 2022 | PMID: 35122944 |
Atypical Childhood-onset Neuroaxonal Dystrophy in an Indian Girl. | Jain S | Journal of pediatric neurosciences | 2019 | PMID: 31516627 |
PLA2G6-associated neurodegeneration: New insights into brain abnormalities and disease progression. | Darling A | Parkinsonism & related disorders | 2019 | PMID: 30340910 |
The structure of iPLA(2)β reveals dimeric active sites and suggests mechanisms of regulation and localization. | Malley KR | Nature communications | 2018 | PMID: 29472584 |
Validation of the finding of hypertrophy of the clava in infantile neuroaxonal dystrophy/PLA2G6 by biometric analysis. | Al-Maawali A | Neuroradiology | 2016 | PMID: 27516098 |
Clinical heterogeneity of PLA2G6-related Parkinsonism: analysis of two Saudi families. | Bohlega SA | BMC research notes | 2016 | PMID: 27268037 |
Genetic Analysis of PLA2G6 in 22 Indian Families with Infantile Neuroaxonal Dystrophy, Atypical Late-Onset Neuroaxonal Dystrophy and Dystonia Parkinsonism Complex. | Kapoor S | PloS one | 2016 | PMID: 27196560 |
Disruption of Golgi morphology and altered protein glycosylation in PLA2G6-associated neurodegeneration. | Davids M | Journal of medical genetics | 2016 | PMID: 26668131 |
PLA2G6-associated Dystonia-Parkinsonism: Case Report and Literature Review. | Karkheiran S | Tremor and other hyperkinetic movements (New York, N.Y.) | 2015 | PMID: 26196026 |
Infantile and childhood onset PLA2G6-associated neurodegeneration in a large North African cohort. | Romani M | European journal of neurology | 2015 | PMID: 25164370 |
Catalytic function of PLA2G6 is impaired by mutations associated with infantile neuroaxonal dystrophy but not dystonia-parkinsonism. | Engel LA | PloS one | 2010 | PMID: 20886109 |
Early-onset L-dopa-responsive parkinsonism with pyramidal signs due to ATP13A2, PLA2G6, FBXO7 and spatacsin mutations. | Paisán-Ruiz C | Movement disorders : official journal of the Movement Disorder Society | 2010 | PMID: 20669327 |
Characterization of PLA2G6 as a locus for dystonia-parkinsonism. | Paisan-Ruiz C | Annals of neurology | 2009 | PMID: 18570303 |
PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron. | Morgan NV | Nature genetics | 2006 | PMID: 16783378 |
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Text-mined citations for rs530348521 ...
HelpRecord last updated Mar 30, 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.