ClinVar Genomic variation as it relates to human health
NM_000492.3(CFTR):c.2175dup (p.Glu726Argfs)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000492.3(CFTR):c.2175dup (p.Glu726Argfs)
Variation ID: 7185 Accession: VCV000007185.46
- Type and length
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Duplication, 1 bp
- Location
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Cytogenetic: 7q31.2 7: 117592340-117592341 (GRCh38) [ NCBI UCSC ] 7: 117232394-117232395 (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 Dec 12, 2017 Oct 8, 2024 Mar 17, 2017 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000492.4:c.2175dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000483.3:p.Glu726fs frameshift NM_000492.3:c.2175dupA NC_000007.14:g.117592342dup NC_000007.13:g.117232396dup NG_016465.4:g.131559dup LRG_663:g.131559dup LRG_663t1:c.2175dup LRG_663p1:p.Glu726fs - Protein change
- E726fs
- Other names
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2307insA
- Canonical SPDI
- NC_000007.14:117592340:AA:AAA
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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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- Links
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
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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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CFTR | - | - |
GRCh38 GRCh37 |
3832 | 5210 |
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 (10) |
reviewed by expert panel
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Mar 17, 2017 | RCV000007605.33 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Oct 25, 2023 | RCV000727574.17 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 17, 2018 | RCV000781235.9 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV001004471.9 | |
Pathogenic (2) |
no assertion criteria provided
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Jun 28, 2024 | RCV001826442.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 7, 2023 | RCV003473035.2 |
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
(Mar 17, 2017)
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reviewed by expert panel
Method: research
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Cystic fibrosis
Affected status: yes
Allele origin:
germline
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CFTR2
Study: CFTR2
Accession: SCV000071474.4 First in ClinVar: Oct 18, 2013 Last updated: Dec 12, 2017 |
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Pathogenic
(Jan 19, 2018)
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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: SCV000854813.1
First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018 |
Number of individuals with the variant: 4
Zygosity: Single Heterozygote
Sex: mixed
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Pathogenic
(Aug 17, 2018)
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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: SCV000919140.1
First in ClinVar: Jun 03, 2019 Last updated: Jun 03, 2019 |
Comment:
Variant summary: CFTR c.2175dupA (p.Glu726ArgfsX4) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: CFTR c.2175dupA (p.Glu726ArgfsX4) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg., p.Leu732X and p.Arg764X). The variant allele was found at a frequency of 1.9e-05 in 1055458 control chromosomes. This frequency is not higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis (1.9e-05 vs 0.013), allowing no conclusion about variant significance. c.2175dupA has been reported in the literature as a homozygous and compound heterozygous allele in numerous individuals affected with Cystic Fibrosis. 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, which showed <10% of normal CFTR mRNA in patient cells (Smit_1993). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Dec 07, 2019)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV001193918.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020 |
Comment:
NM_000492.3(CFTR):c.2175dupA(E726Rfs*4, aka 2307insA) is classified as pathogenic in the context of cystic fibrosis and is associated with the classic form of disease. Sources cited for … (more)
NM_000492.3(CFTR):c.2175dupA(E726Rfs*4, aka 2307insA) is classified as pathogenic in the context of cystic fibrosis and is associated with the classic form of disease. Sources cited for classification include the following: PMID 23974870. Classification of NM_000492.3(CFTR):c.2175dupA(E726Rfs*4, aka 2307insA) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. (less)
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Pathogenic
(Nov 05, 2018)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
Affected status: yes
Allele origin:
unknown
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Mendelics
Accession: SCV000886215.2
First in ClinVar: Apr 12, 2018 Last updated: Dec 11, 2022 |
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Pathogenic
(Oct 25, 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: SCV004563422.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
The CFTR c.2175dup; p.Glu726ArgfsTer4 variant (rs746418935) is reported in the literature in individuals affected with cystic fibrosis (Smit 1993, Sosnay 2013, Sugarman 2004). This variant … (more)
The CFTR c.2175dup; p.Glu726ArgfsTer4 variant (rs746418935) is reported in the literature in individuals affected with cystic fibrosis (Smit 1993, Sosnay 2013, Sugarman 2004). This variant is reported in ClinVar (Variation ID: 7185) and is found in the African population with an allele frequency of 0.03% (8/24,954 alleles) in the Genome Aggregation Database. This variant causes a frameshift by inserting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Furthermore, in vitro functional assays show a significant reduction in transcript expression (Smit 1993). Based on available information, this variant is considered to be pathogenic. References: Smit LS et al. An African-American cystic fibrosis patient homozygous for a novel frameshift mutation associated with reduced CFTR mRNA levels. Hum Mutat. 1993;2(2):148-51. PMID: 7686423. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013 Oct;45(10):1160-7. PMID: 23974870. Sugarman EA et al. CFTR mutation distribution among U.S. Hispanic and African American individuals: evaluation in cystic fibrosis patient and carrier screening populations. Genet Med. 2004 Sep-Oct;6(5):392-9. PMID: 15371903. (less)
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Pathogenic
(Sep 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004847339.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Glu726ArgfsX4 variant in CFTR is commonly reported in individuals of African American ancestry and has been identified in the homozygous or compound heterozygous state … (more)
The p.Glu726ArgfsX4 variant in CFTR is commonly reported in individuals of African American ancestry and has been identified in the homozygous or compound heterozygous state with other disease-causing variants in CFTR in at least 2 individuals with clinical features of cystic fibrosis (Smit 1993 PMID: 7686423, Sugarman 2004 PMID: 15371903, Souza 2020 PMID: 32674983). In addition, it has been found in 59 patients in the CFTR2 database, the majority of which are pancreatic insufficient. This variant has also been reported by other clinical laboratories in ClinVar ((Variation ID 7185) and has been identified in 0.02% (9/41432) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 726 and leads to a premature termination codon 4 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Biallelic loss of function of the CFTR gene is an established disease mechanism in autosomal recessive cystic fibrosis. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive cystic fibrosis. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3. (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Congenital bilateral aplasia of vas deferens from CFTR mutation
Cystic fibrosis
Affected status: unknown
Allele origin:
germline
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Baylor Genetics
Accession: SCV001163516.1
First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020 |
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Pathogenic
(Jan 29, 2018)
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criteria provided, single submitter
Method: curation
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cystic fibrosis
Affected status: yes
Allele origin:
germline
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CFTR-France
Accession: SCV001169544.1
First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020 |
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Pathogenic
(Jun 18, 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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001714843.1
First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021 |
Number of individuals with the variant: 1
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Pathogenic
(Jul 14, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
Affected status: unknown
Allele origin:
germline
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Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV004024551.2
First in ClinVar: Aug 19, 2023 Last updated: Nov 11, 2023 |
Comment:
Disease-causing CFTR variant. See www.CFTR2.org for phenotype information.
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Pathogenic
(Nov 29, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001582512.4
First in ClinVar: May 10, 2021 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Glu726Argfs*4) in the CFTR gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Glu726Argfs*4) in the CFTR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922). This variant is present in population databases (rs746418935, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with cystic fibrosis (PMID: 7686423, 15371903, 18456578). It is commonly reported in individuals of African American ancestry (PMID: 7686423, 15371903, 18456578). This variant is also known as c.2307insA. ClinVar contains an entry for this variant (Variation ID: 7185). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(May 24, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002727273.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.2175dupA pathogenic mutation, located in coding exon 14 of the CFTR gene, results from a duplication of A at nucleotide position 2175, causing a … (more)
The c.2175dupA pathogenic mutation, located in coding exon 14 of the CFTR gene, results from a duplication of A at nucleotide position 2175, causing a translational frameshift with a predicted alternate stop codon (p.E726Rfs*4). This mutation was described in the homozygous state in an African American individual with pancreatic insufficient cystic fibrosis, elevated sweat chloride levels, and severe lung disease (Smit LS et al. Hum. Mutat., 1993;2:148-51). The overall frequency of this allele in CF chromosomes has been observed at approximately 0.2%, with the highest occurrence in 2.0% of all African American CF chromosomes (Macek M et al. Am. J. Hum. Genet., 1997 May;60:1122-7; Bobadilla JL et al. Hum. Mutat., 2002 Jun;19:575-606). This pathogenic mutation is associated with elevated sweat chloride levels and pancreatic insufficiency (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). Of note, this alteration is also known as 2307insA in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Nov 07, 2023)
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criteria provided, single submitter
Method: clinical testing
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Bronchiectasis with or without elevated sweat chloride 1
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004213406.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Pathogenic
(Jan 01, 1993)
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no assertion criteria provided
Method: literature only
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CYSTIC FIBROSIS
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000027806.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 12, 2018 |
Comment on evidence:
By chemical mismatch cleavage in an African American patient with cystic fibrosis (CF; 219700), Smit et al. (1993) found homozygosity for insertion of an adenine … (more)
By chemical mismatch cleavage in an African American patient with cystic fibrosis (CF; 219700), Smit et al. (1993) found homozygosity for insertion of an adenine after nucleotide 2307 in exon 13. The resulting shift of the reading frame at codon 726 introduced 2 consecutive stop codons at amino acid positions 729 and 730. To examine the mRNA level associated with the 2307insA mutation, RNA from nasal epithelial cells of the patient and a normal subject were reverse transcribed. Subsequent amplification of the cDNA demonstrated that the CFTR message level associated with 2307insA was markedly reduced compared to the normal control, while both the patient and the normal subject showed similar levels of expression. (less)
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Pathogenic
(Mar 17, 2017)
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no assertion criteria provided
Method: clinical testing
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CFTR-related disorders
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002080718.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
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Pathogenic
(Jun 28, 2024)
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no assertion criteria provided
Method: clinical testing
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CFTR-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV005352507.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The CFTR c.2175dupA variant is predicted to result in a frameshift and premature protein termination (p.Glu726Argfs*4). This variant, also referred to as c.2307insA in the … (more)
The CFTR c.2175dupA variant is predicted to result in a frameshift and premature protein termination (p.Glu726Argfs*4). This variant, also referred to as c.2307insA in the literature, has been reported in patients with cystic fibrosis (Smit et al. 1993. PubMed ID: 7686423; Table 2 in Castellani et al. 2008. PubMed ID: 18456578; Souza et al. 2020. PubMed ID: 32674983). This variant has been interpreted as pathogenic by the CFTR2 expert review panel in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/7185). This variant is reported in 0.032% of alleles in individuals of African descent in gnomAD. Frameshift variants in CFTR are expected to be pathogenic. Based on this evidence, we interpret this variant as pathogenic. (less)
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not provided
(-)
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no classification provided
Method: phenotyping only
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Cystic fibrosis
Affected status: unknown
Allele origin:
unknown
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GenomeConnect, ClinGen
Accession: SCV001338858.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant interpretted as Pathogenic and reported on 01-07-2016 by Lab or GTR ID 500068. GenomeConnect assertions are reported exactly as they appear on the patient-provided … (more)
Variant interpretted as Pathogenic and reported on 01-07-2016 by Lab or GTR ID 500068. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Abnormal delivery (present) , Abnormality of the umbilical cord (present) , Anxiety (present) , Abnormality of cardiovascular system morphology (present) , Abnormal thrombosis (present) , … (more)
Abnormal delivery (present) , Abnormality of the umbilical cord (present) , Anxiety (present) , Abnormality of cardiovascular system morphology (present) , Abnormal thrombosis (present) , Abnormality of coagulation (present) (less)
Indication for testing: Not Provided
Age: 30-39 years
Sex: female
Testing laboratory: Mayo Clinic Laboratories,Mayo Clinic
Date variant was reported to submitter: 2016-01-07
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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K162E - A rare and uncategorized CFTR variant causing cystic fibrosis. | Souza EL | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2021 | PMID: 32674983 |
Next-generation carrier screening. | Umbarger MA | Genetics in medicine : official journal of the American College of Medical Genetics | 2014 | PMID: 23765052 |
Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. | Sosnay PR | Nature genetics | 2013 | PMID: 23974870 |
An empirical estimate of carrier frequencies for 400+ causal Mendelian variants: results from an ethnically diverse clinical sample of 23,453 individuals. | Lazarin GA | Genetics in medicine : official journal of the American College of Medical Genetics | 2013 | PMID: 22975760 |
Mutation nomenclature in practice: findings and recommendations from the cystic fibrosis external quality assessment scheme. | Berwouts S | Human mutation | 2011 | PMID: 21796730 |
Cystic fibrosis carrier testing in an ethnically diverse US population. | Rohlfs EM | Clinical chemistry | 2011 | PMID: 21474639 |
Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice. | Castellani C | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2008 | PMID: 18456578 |
CFTR mutation distribution among U.S. Hispanic and African American individuals: evaluation in cystic fibrosis patient and carrier screening populations. | Sugarman EA | Genetics in medicine : official journal of the American College of Medical Genetics | 2004 | PMID: 15371903 |
Cystic fibrosis population carrier screening: 2004 revision of American College of Medical Genetics mutation panel. | Watson MS | Genetics in medicine : official journal of the American College of Medical Genetics | 2004 | PMID: 15371902 |
Cystic fibrosis: a worldwide analysis of CFTR mutations--correlation with incidence data and application to screening. | Bobadilla JL | Human mutation | 2002 | PMID: 12007216 |
Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis. | Cohn JA | The New England journal of medicine | 1998 | PMID: 9725922 |
Identification of common cystic fibrosis mutations in African-Americans with cystic fibrosis increases the detection rate to 75%. | Macek M Jr | American journal of human genetics | 1997 | PMID: 9150159 |
Molecular basis of defective anion transport in L cells expressing recombinant forms of CFTR. | Yang Y | Human molecular genetics | 1993 | PMID: 7691345 |
An African-American cystic fibrosis patient homozygous for a novel frameshift mutation associated with reduced CFTR mRNA levels. | Smit LS | Human mutation | 1993 | PMID: 7686423 |
A cluster of cystic fibrosis mutations in the first nucleotide-binding fold of the cystic fibrosis conductance regulator protein. | Cutting GR | Nature | 1990 | PMID: 1695717 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CFTR | - | - | - | - |
https://cftr2.org | - | - | - | - |
https://cftr2.org/ | - | - | - | - |
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Text-mined citations for rs746418935 ...
HelpRecord last updated Nov 25, 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.