ClinVar Genomic variation as it relates to human health
NM_031448.6(C19orf12):c.391A>G (p.Lys131Glu)
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.
Uncertain significance(4); Benign(2); Likely benign(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_031448.6(C19orf12):c.391A>G (p.Lys131Glu)
Variation ID: 31158 Accession: VCV000031158.46
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19q12 19: 29702747 (GRCh38) [ NCBI UCSC ] 19: 30193654 (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 Jan 13, 2017 Apr 15, 2024 Jan 22, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_031448.6:c.391A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_113636.2:p.Lys131Glu missense NM_001031726.4:c.391A>G NP_001026896.3:p.Lys131Glu missense NM_001256046.3:c.*12A>G 3 prime UTR NM_001256047.2:c.391A>G NP_001242976.1:p.Lys131Glu missense NM_001282929.1:c.199A>G NP_001269858.1:p.Lys67Glu missense NM_001282930.3:c.199A>G NP_001269859.1:p.Lys67Glu missense NM_001282931.3:c.199A>G NP_001269860.1:p.Lys67Glu missense NC_000019.10:g.29702747T>C NC_000019.9:g.30193654T>C NG_031970.2:g.18043A>G - Protein change
- K142E, K131E, K67E
- Other names
- C19ORF12, LYS142GLU
- Canonical SPDI
- NC_000019.10:29702746: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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0.00220 (C)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00094
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00123
Trans-Omics for Precision Medicine (TOPMed) 0.00124
1000 Genomes Project 30x 0.00172
1000 Genomes Project 0.00220
The Genome Aggregation Database (gnomAD), exomes 0.00229
Exome Aggregation Consortium (ExAC) 0.00244
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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C19orf12 | - | - |
GRCh38 GRCh37 |
277 | 318 |
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
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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Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Dec 3, 2021 | RCV000024154.11 | |
no classifications from unflagged records (1) |
no classifications from unflagged records
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Apr 7, 2022 | RCV000415210.4 | |
not provided (1) |
no classification provided
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- | RCV000509226.2 | |
Likely benign (5) |
criteria provided, multiple submitters, no conflicts
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May 1, 2023 | RCV000553096.24 | |
Uncertain significance (1) |
criteria provided, single submitter
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Aug 7, 2018 | RCV000714889.4 | |
Benign/Likely benign (2) |
criteria provided, multiple submitters, no conflicts
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Jan 22, 2024 | RCV001083182.9 | |
Benign (1) |
criteria provided, single submitter
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Dec 11, 2023 | RCV001844017.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 31, 2017 | RCV001847623.4 |
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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Uncertain significance
(Aug 07, 2018)
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criteria provided, single submitter
Method: clinical testing
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Neurodegeneration with brain iron accumulation 4
Affected status: no
Allele origin:
inherited
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Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV000845637.1
First in ClinVar: Nov 03, 2018 Last updated: Nov 03, 2018 |
Number of individuals with the variant: 1
Sex: female
Geographic origin: Iran
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Uncertain significance
(Aug 07, 2018)
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criteria provided, single submitter
Method: clinical testing
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Spastic paraplegia 5A
Affected status: no
Allele origin:
inherited
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Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV000845636.1
First in ClinVar: Nov 03, 2018 Last updated: Nov 03, 2018 |
Number of individuals with the variant: 1
Sex: female
Geographic origin: Iran
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Likely benign
(Jan 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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Hereditary spastic paraplegia 43
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001440130.1
First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020 |
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Likely benign
(Jan 25, 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: SCV001803233.1
First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
Comment:
This variant is associated with the following publications: (PMID: 30088953, 21981780, 25592411)
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Uncertain significance
(Jan 31, 2017)
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criteria provided, single submitter
Method: clinical testing
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Hereditary spastic paraplegia
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV002104503.1
First in ClinVar: Mar 19, 2022 Last updated: Mar 19, 2022 |
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Benign
(Jan 22, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hereditary spastic paraplegia 43
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000647094.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
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Uncertain significance
(Dec 03, 2021)
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criteria provided, single submitter
Method: clinical testing
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Neurodegeneration with brain iron accumulation 4
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001141042.2
First in ClinVar: Jan 09, 2020 Last updated: Dec 12, 2021 |
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Benign
(Dec 11, 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: SCV002103566.2
First in ClinVar: Mar 12, 2022 Last updated: Feb 04, 2024 |
Comment:
Variant summary: C19orf12 c.391A>G (p.Lys131Glu) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign … (more)
Variant summary: C19orf12 c.391A>G (p.Lys131Glu) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0023 in 250744 control chromosomes, predominantly at a frequency of 0.0096 within the South Asian subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 16 fold of the estimated maximal expected allele frequency for a pathogenic variant in C19orf12 causing Neurodegeneration With Brain Iron Accumulation phenotype (0.0006), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments: benign (n=1), likely benign (n=3), uncertain significance (n=3) and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as benign. (less)
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Likely benign
(May 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001151760.21
First in ClinVar: Feb 03, 2020 Last updated: Apr 15, 2024 |
Comment:
C19orf12: PM3, PM2:Supporting, BP4, BS2
Number of individuals with the variant: 5
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Likely benign
(-)
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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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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001743246.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
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Likely benign
(-)
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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, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001931725.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Likely benign
(-)
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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: SCV001973835.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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not provided
(-)
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no classification provided
Method: phenotyping only
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Neurodegeneration with brain iron accumulation 4
Hereditary spastic paraplegia 43
Affected status: unknown
Allele origin:
unknown
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GenomeConnect, ClinGen
Accession: SCV000607239.1
First in ClinVar: Oct 16, 2017 Last updated: Oct 16, 2017 |
Comment:
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 … (more)
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:
Premature birth (present) , Abnormal delivery (present) , Hypermetropia (present) , Vertigo (present) , Pectus carinatum (present) , Hip dysplasia (present) , Joint hypermobility (present) … (more)
Premature birth (present) , Abnormal delivery (present) , Hypermetropia (present) , Vertigo (present) , Pectus carinatum (present) , Hip dysplasia (present) , Joint hypermobility (present) , Abnormality of the curvature of the vertebral column (present) , Gastrointestinal dysmotility (present) , Abnormality of the stomach (present) , Abnormality of the bladder (present) (less)
Indication for testing: Diagnostic
Age: 0-9 years
Sex: female
Method: Sanger Sequencing
Testing laboratory: GeneDx
Date variant was reported to submitter: 2017-01-04
Testing laboratory interpretation: Uncertain significance
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Pathogenic
(Jul 01, 2015)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Older claim that does not account for recent evidence
Source: ClinGen
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Adult-onset night blindness
Dystonic disorder Mental deterioration Peripheral visual field loss Tremor
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV000492734.1
First in ClinVar: Jan 13, 2017 Last updated: Jan 13, 2017 |
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Pathogenic
(Oct 07, 2011)
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Flagged submission
flagged submission
Method: literature only
Reason: Older claim that does not account for recent evidence
Source: ClinGen
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NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 4, AUTOSOMAL RECESSIVE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000045445.3
First in ClinVar: Apr 04, 2013 Last updated: Jul 22, 2019 |
Comment on evidence:
In a Polish patient with neurodegeneration with brain iron accumulation-4 (NBIA4; 614298), Hartig et al. (2011) identified compound heterozygosity for 2 mutations in the C19ORF12 … (more)
In a Polish patient with neurodegeneration with brain iron accumulation-4 (NBIA4; 614298), Hartig et al. (2011) identified compound heterozygosity for 2 mutations in the C19ORF12 gene: a c.424A-G transition (c.424A-G, NM_001031726.2), resulting in a lys142-to-glu (K142E) substitution and G69R (614297.0003). Neither mutation was found in 750 control chromosomes. This patient had a relatively mild form of the disorder, with only impairment of fine motor skills beginning at age 14 years. MRI performed at age 12 for a pituitary adenoma showed brain iron accumulation as an incidental finding. This same genotype (G69R and K142E) was found in 1 of 676 patients with parkinsonism. This patient presented with paranoid hallucinations at age 25 years. By age 49, he was diagnosed with Parkinson disease, with rigidity, akinesia, and mild tremor. He also had axial signs, dystonia of the legs with muscle cramps, hypophonia, hypomimia, vivid dreams, sleep disturbance, optic hallucinations, and cognitive decline. CT scan showed marked cerebral atrophy, but MRI was not performed. Both of these patients had a milder form of the disorder compared to patients with other C19ORF12 mutations. (less)
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
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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Absence of an orphan mitochondrial protein, c19orf12, causes a distinct clinical subtype of neurodegeneration with brain iron accumulation. | Hartig MB | American journal of human genetics | 2011 | PMID: 21981780 |
Text-mined citations for rs146170087 ...
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.