ClinVar Genomic variation as it relates to human health
NM_001171.6(ABCC6):c.3940C>T (p.Arg1314Trp)
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_001171.6(ABCC6):c.3940C>T (p.Arg1314Trp)
Variation ID: 6564 Accession: VCV000006564.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16p13.11 16: 16154974 (GRCh38) [ NCBI UCSC ] 16: 16248831 (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 Aug 21, 2017 Feb 14, 2024 Jan 30, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001171.6:c.3940C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001162.5:p.Arg1314Trp missense NM_001351800.1:c.3598C>T NP_001338729.1:p.Arg1200Trp missense NR_147784.1:n.3602C>T non-coding transcript variant NC_000016.10:g.16154974G>A NC_000016.9:g.16248831G>A NG_007558.3:g.73644C>T LRG_1115:g.73644C>T LRG_1115t1:c.3940C>T LRG_1115p1:p.Arg1314Trp O95255:p.Arg1314Trp - Protein change
- R1314W, R1200W
- Other names
- -
- Canonical SPDI
- NC_000016.10:16154973: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.
1000 Genomes Project 0.00020
1000 Genomes Project 30x 0.00047
Exome Aggregation Consortium (ExAC) 0.00048
Trans-Omics for Precision Medicine (TOPMed) 0.00067
The Genome Aggregation Database (gnomAD) 0.00069
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
Help
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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ABCC6 | - | - |
GRCh38 GRCh38 GRCh37 |
1441 | 1798 |
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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Pathogenic (2) |
no assertion criteria provided
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Mar 1, 2021 | RCV000006942.9 | |
Pathogenic (1) |
no assertion criteria provided
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Jan 13, 2012 | RCV000023273.6 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 30, 2024 | RCV000254915.8 | |
Pathogenic (1) |
criteria provided, single submitter
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May 17, 2022 | RCV001535919.3 |
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 26, 2022)
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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: SCV000321369.8
First in ClinVar: Oct 09, 2016 Last updated: Dec 11, 2022 |
Comment:
Published functional studies demonstrate a damaging effect with R1314W resulting in abnormal protein trafficking and inappropriate intracellular accumulation (Le Saux et al., 2011); In silico … (more)
Published functional studies demonstrate a damaging effect with R1314W resulting in abnormal protein trafficking and inappropriate intracellular accumulation (Le Saux et al., 2011); 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: 16392638, 22209248, 10835642, 30537162, 34205333, 34906475, 21935449, 24008425, 19339160, 24352041, 23483032, 27994049, 28102862, 28416300, 27826008, 32445016, 31589614, 34440381, 33005041, 32873932) (less)
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Pathogenic
(May 17, 2022)
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criteria provided, single submitter
Method: clinical testing
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Pseudoxanthoma elasticum, forme fruste
Autosomal recessive inherited pseudoxanthoma elasticum Arterial calcification, generalized, of infancy, 2
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV001752567.2
First in ClinVar: Jul 18, 2021 Last updated: Dec 31, 2022 |
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Pathogenic
(Jan 30, 2024)
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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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Invitae
Accession: SCV001587439.4
First in ClinVar: May 10, 2021 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 1314 of the ABCC6 protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1314 of the ABCC6 protein (p.Arg1314Trp). This variant is present in population databases (rs63750759, gnomAD 0.3%). This missense change has been observed in individuals with pseudoxanthoma elasticum (PMID: 10835642, 16835894, 19339160, 30537162). ClinVar contains an entry for this variant (Variation ID: 6564). 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 expected to disrupt ABCC6 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ABCC6 function (PMID: 21935449, 23483032, 27994049). This variant disrupts the p.Arg1314 amino acid residue in ABCC6. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 29722917). 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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Pathogenic
(Jan 13, 2012)
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no assertion criteria provided
Method: literature only
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PSEUDOXANTHOMA ELASTICUM
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000027138.5
First in ClinVar: Apr 04, 2013 Last updated: Dec 15, 2018 |
Comment on evidence:
Pseudoxanthoma Elasticum In a patient with autosomal recessive pseudoxanthoma elasticum (PXE; 264800), Le Saux et al. (2000) identified a C-to-T transition at nucleotide 3940 of … (more)
Pseudoxanthoma Elasticum In a patient with autosomal recessive pseudoxanthoma elasticum (PXE; 264800), Le Saux et al. (2000) identified a C-to-T transition at nucleotide 3940 of the ABCC6 gene, resulting in an arg-to-trp substitution at codon 1314 (R1314W). This mutation was found in homozygosity in one family. Generalized Arterial Calcification of Infancy 2 In a 5-year-old boy with generalized arterial calcification of infancy (GACI2; 614473), Nitschke et al. (2012) identified homozygosity for the R1314W mutation. The boy was born as the first of dizygotic twins, and his twin brother was unaffected. The patient had calcification of the aorta and pulmonary, coronary, and renal arteries as well as other arteries, and stippled calcifications of proximal epiphyses of humeri, femora, pelvic cartilage, larynx, and mandible. He had severely decreased biventricular systolic function, marked cardiomegaly, and severe mitral insufficiency, as well as hypertension and respiratory insufficiency. Cerebral MRI revealed diffuse white matter disease, with cystic encephalomalacia, and laboratory analysis showed hyperbilirubinemia, anemia, and thrombocytopenia. Nitschke et al. (2012) also identified the R1314W mutation in compound heterozygosity in 2 unrelated GACI patients, a French female infant who died at 6 weeks of age and also carried an R1141X mutation (603234.0001), and an Afro-Caribbean male infant who died at 8 weeks of age with generalized arterial stenosis, myocardial infarction, and hypertension and also carried a 1-bp insertion (450insC; 603234.0028) in exon 4 of the ABCC6 gene, predicted to result in a premature stop codon and a truncated protein. In addition, in a 3-year-old South African girl with GACI, Nitschke et al. (2012) identified only a heterozygous R1314W mutation, but noted that mutations in regulatory untranslated regions of ABCC6 might not have been detected by their technique. In the South African child, onset of symptoms occurred at 2.5 years of age, and included calcification of the aorta, spleen, and pancreas, nephrocalcinosis, failure to thrive, hypertension, and heart failure. (less)
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Pathogenic
(Jan 13, 2012)
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no assertion criteria provided
Method: literature only
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ARTERIAL CALCIFICATION, GENERALIZED, OF INFANCY, 2
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000044564.5
First in ClinVar: Apr 04, 2013 Last updated: Dec 15, 2018 |
Comment on evidence:
Pseudoxanthoma Elasticum In a patient with autosomal recessive pseudoxanthoma elasticum (PXE; 264800), Le Saux et al. (2000) identified a C-to-T transition at nucleotide 3940 of … (more)
Pseudoxanthoma Elasticum In a patient with autosomal recessive pseudoxanthoma elasticum (PXE; 264800), Le Saux et al. (2000) identified a C-to-T transition at nucleotide 3940 of the ABCC6 gene, resulting in an arg-to-trp substitution at codon 1314 (R1314W). This mutation was found in homozygosity in one family. Generalized Arterial Calcification of Infancy 2 In a 5-year-old boy with generalized arterial calcification of infancy (GACI2; 614473), Nitschke et al. (2012) identified homozygosity for the R1314W mutation. The boy was born as the first of dizygotic twins, and his twin brother was unaffected. The patient had calcification of the aorta and pulmonary, coronary, and renal arteries as well as other arteries, and stippled calcifications of proximal epiphyses of humeri, femora, pelvic cartilage, larynx, and mandible. He had severely decreased biventricular systolic function, marked cardiomegaly, and severe mitral insufficiency, as well as hypertension and respiratory insufficiency. Cerebral MRI revealed diffuse white matter disease, with cystic encephalomalacia, and laboratory analysis showed hyperbilirubinemia, anemia, and thrombocytopenia. Nitschke et al. (2012) also identified the R1314W mutation in compound heterozygosity in 2 unrelated GACI patients, a French female infant who died at 6 weeks of age and also carried an R1141X mutation (603234.0001), and an Afro-Caribbean male infant who died at 8 weeks of age with generalized arterial stenosis, myocardial infarction, and hypertension and also carried a 1-bp insertion (450insC; 603234.0028) in exon 4 of the ABCC6 gene, predicted to result in a premature stop codon and a truncated protein. In addition, in a 3-year-old South African girl with GACI, Nitschke et al. (2012) identified only a heterozygous R1314W mutation, but noted that mutations in regulatory untranslated regions of ABCC6 might not have been detected by their technique. In the South African child, onset of symptoms occurred at 2.5 years of age, and included calcification of the aorta, spleen, and pancreas, nephrocalcinosis, failure to thrive, hypertension, and heart failure. (less)
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Pathogenic
(Mar 01, 2021)
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no assertion criteria provided
Method: research
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Autosomal recessive inherited pseudoxanthoma elasticum
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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PXE International
Accession: SCV000589091.2
First in ClinVar: Aug 21, 2017 Last updated: Mar 07, 2021 |
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
Papule (present) , Skin plaque (present) , Angioid streaks (present)
Tissue: blood
Method: sanger sequencing
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Papule (present) , Skin plaque (present) , Angioid streaks (present) , Weak or absent arterial pulse (present)
Tissue: blood
Method: sanger sequencing
Observation 3:
Number of individuals with the variant: 1
Clinical Features:
Papule (present) , Angioid streaks (present) , Vascular surgery (present)
Tissue: blood
Method: sanger sequencing
Observation 4:
Number of individuals with the variant: 1
Clinical Features:
Papule (present) , Retinal hemorrhage (present)
Tissue: blood
Method: sanger sequencing
Observation 5:
Number of individuals with the variant: 1
Clinical Features:
Papule (present) , Skin plaque (present)
Tissue: blood
Method: sanger sequencing
Observation 6:
Number of individuals with the variant: 1
Clinical Features:
Nephrolithiasis (present) , Papule (present) , Skin plaque (present) , Angioid streaks (present)
Tissue: blood
Method: sanger sequencing
Observation 7:
Number of individuals with the variant: 1
Clinical Features:
Nephrolithiasis (present) , Papule (present) , Skin plaque (present) , Angioid streaks (present)
Tissue: blood
Method: sanger sequencing
Observation 8:
Number of individuals with the variant: 1
Clinical Features:
Papule (present) , Skin plaque (present) , Angioid streaks (present) , Angina pectoris (present) , Abnormal EKG (present)
Tissue: blood
Method: sanger sequencing
Observation 9:
Number of individuals with the variant: 1
Clinical Features:
Nephrolithiasis (present) , Papule (present) , Skin plaque (present) , Angioid streaks (present) , Intermittent claudication (present)
Tissue: blood
Method: sanger sequencing
Observation 10:
Number of individuals with the variant: 1
Clinical Features:
Papule (present) , Skin plaque (present)
Tissue: blood
Method: sanger sequencing
Observation 11:
Number of individuals with the variant: 1
Clinical Features:
Papule (present) , Skin plaque (present)
Tissue: blood
Method: sanger sequencing
Observation 12:
Number of individuals with the variant: 1
Clinical Features:
Abnormally lax or hyperextensible skin (present) , Retinal hemorrhage (present) , Intermittent claudication (present)
Tissue: blood
Method: sanger sequencing
Observation 13:
Number of individuals with the variant: 1
Clinical Features:
Abnormally lax or hyperextensible skin (present) , Retinal hemorrhage (present) , Intermittent claudication (present)
Tissue: blood
Method: sanger sequencing
Observation 14:
Number of individuals with the variant: 1
Clinical Features:
Papule (present) , Angioid streaks (present)
Tissue: blood
Method: sanger sequencing
Observation 15:
Number of individuals with the variant: 1
Clinical Features:
Papule (present) , Skin plaque (present) , Weak or absent arterial pulse (present)
Age: 0-9 years
Ethnicity/Population group: .
Tissue: blood
Method: sanger sequencing
Observation 16:
Number of individuals with the variant: 1
Clinical Features:
Papule (present) , Skin plaque (present) , Weak or absent arterial pulse (present)
Age: 0-9 years
Ethnicity/Population group: .
Tissue: blood
Method: sanger sequencing
Observation 17:
Number of individuals with the variant: 1
Clinical Features:
Papule (present) , Skin plaque (present) , Retinal hemorrhage (present) , Weak or absent arterial pulse (present)
Age: 0-9 years
Ethnicity/Population group: .
Tissue: blood
Method: sanger sequencing
Observation 18:
Number of individuals with the variant: 1
Clinical Features:
Papule (present) , Skin plaque (present) , Retinal hemorrhage (present) , Weak or absent arterial pulse (present)
Age: 0-9 years
Ethnicity/Population group: .
Tissue: blood
Method: sanger sequencing
Observation 19:
Number of individuals with the variant: 1
Age: 0-9 years
Ethnicity/Population group: .
Tissue: blood
Method: sanger sequencing
Observation 20:
Number of individuals with the variant: 1
Age: 0-9 years
Ethnicity/Population group: .
Tissue: blood
Method: sanger sequencing
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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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Reassessment of causality of ABCC6 missense variants associated with pseudoxanthoma elasticum based on Sherloc. | Verschuere S | Genetics in medicine : official journal of the American College of Medical Genetics | 2021 | PMID: 32873932 |
Classic pseudoxanthoma elasticum in a girl with sickle cell disease. | Mitre V | Pediatric dermatology | 2019 | PMID: 30537162 |
Pathogenic variants in the ABCC6 gene are associated with an increased risk for ischemic stroke. | De Vilder EYG | Brain pathology (Zurich, Switzerland) | 2018 | PMID: 29722917 |
Mutation spectrum in the ABCC6 gene and genotype-phenotype correlations in a French cohort with pseudoxanthoma elasticum. | Legrand A | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 28102862 |
Stabilization of Nucleotide Binding Domain Dimers Rescues ABCC6 Mutants Associated with Pseudoxanthoma Elasticum. | Ran Y | The Journal of biological chemistry | 2017 | PMID: 27994049 |
Transcriptional regulation of the ABCC6 gene and the background of impaired function of missense disease-causing mutations. | Arányi T | Frontiers in genetics | 2013 | PMID: 23483032 |
Generalized arterial calcification of infancy and pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6. | Nitschke Y | American journal of human genetics | 2012 | PMID: 22209248 |
Expression and in vivo rescue of human ABCC6 disease-causing mutants in mouse liver. | Le Saux O | PloS one | 2011 | PMID: 21935449 |
Spectrum of genetic variation at the ABCC6 locus in South Africans: Pseudoxanthoma elasticum patients and healthy individuals. | Ramsay M | Journal of dermatological science | 2009 | PMID: 19339160 |
Mutational analysis of the ABCC6 gene and the proximal ABCC6 gene promoter in German patients with pseudoxanthoma elasticum (PXE). | Schulz V | Human mutation | 2006 | PMID: 16835894 |
Mutations in a gene encoding an ABC transporter cause pseudoxanthoma elasticum. | Le Saux O | Nature genetics | 2000 | PMID: 10835642 |
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Text-mined citations for rs63750759 ...
HelpRecord last updated Feb 20, 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.