ClinVar Genomic variation as it relates to human health
NM_000138.5(FBN1):c.364C>T (p.Arg122Cys)
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_000138.5(FBN1):c.364C>T (p.Arg122Cys)
Variation ID: 16440 Accession: VCV000016440.27
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q21.1 15: 48600217 (GRCh38) [ NCBI UCSC ] 15: 48892414 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 Feb 28, 2024 Oct 13, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000138.5:c.364C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000129.3:p.Arg122Cys missense NC_000015.10:g.48600217G>A NC_000015.9:g.48892414G>A NG_008805.2:g.50572C>T LRG_778:g.50572C>T LRG_778t1:c.364C>T LRG_778p1:p.Arg122Cys - Protein change
- R122C
- Other names
- p.R122C:CGC>TGC
- Canonical SPDI
- NC_000015.10:48600216:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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FBN1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
7436 | 7765 |
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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
no assertion criteria provided
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Aug 1, 1994 | RCV000017902.34 | |
Pathogenic (2) |
criteria provided, single submitter
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Aug 18, 2011 | RCV000029732.11 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 18, 2022 | RCV000181647.15 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 1, 2017 | RCV000626614.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 13, 2018 | RCV001000178.15 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 13, 2023 | RCV001201375.14 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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May 17, 2019 | RCV001798007.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 23, 2021 | RCV002496395.8 |
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
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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
(Jan 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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Aortic dissection
Arachnodactyly High palate Lens subluxation
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV000747315.1
First in ClinVar: May 12, 2018 Last updated: May 12, 2018 |
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Pathogenic
(Aug 13, 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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001156669.1
First in ClinVar: Feb 10, 2020 Last updated: Feb 10, 2020 |
Comment:
The FBN1 c.364C>T; p.Arg122Cys variant (rs137854467) has been reported in multiple families with clinical symptoms suggestive of Marfan syndrome, and is strongly associated with ectopia … (more)
The FBN1 c.364C>T; p.Arg122Cys variant (rs137854467) has been reported in multiple families with clinical symptoms suggestive of Marfan syndrome, and is strongly associated with ectopia lentis (Black 1998, Comeglio 2002, Jin 2007, Loeys 2001, Stahl-Hallengran 1994). It is reported in ClinVar as pathogenic (Variation ID: 16440) and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The variant changes an arginine in an EGF-like domain into a cysteine residue, which meets the revised Ghent nosology criteria of a causative Marfan syndrome variant (Loeys 2010). Based on available information, this variant is considered to be pathogenic. References: Black C et al. Correlation of a recurrent FBN1 mutation (R122C) with an atypical familial Marfan syndrome phenotype. Hum Mutat. 1998; Suppl 1:S198-200. Comeglio P et al. Identification of FBN1 gene mutations in patients with ectopia lentis and marfanoid habitus. Br J Ophthalmol. 2002; 86(12):1359-62. Jin C et al. Novel FBN1 mutations associated with predominant ectopia lentis and marfanoid habitus in Chinese patients. Mol Vis. 2007; 13:1280-4. Loeys B et al. Genotype and phenotype analysis of 171 patients referred for molecular study of the fibrillin-1 gene FBN1 because of suspected Marfan syndrome. Arch Intern Med. 2001; 2001 Nov 12;161(20):2447-54. Loeys B et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet. 2010; 47(7):476-85. Stahl-Hallengren C et al. An extra cysteine in one of the non-calcium-binding epidermal growth factor-like motifs of the FBN1 polypeptide is connected to a novel variant of Marfan syndrome. J Clin Invest. 1994; 94(2):709-13. (less)
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Pathogenic
(Nov 05, 2014)
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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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Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001450112.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Number of individuals with the variant: 1
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Pathogenic
(May 17, 2019)
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criteria provided, single submitter
Method: clinical testing
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Familial thoracic aortic aneurysm and aortic dissection
Affected status: unknown
Allele origin:
germline
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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV002041974.1
First in ClinVar: Dec 29, 2021 Last updated: Dec 29, 2021 |
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Pathogenic
(Aug 23, 2021)
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criteria provided, single submitter
Method: clinical testing
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Acromicric dysplasia
Ectopia lentis 1, isolated, autosomal dominant Marfan syndrome Stiff skin syndrome MASS syndrome Weill-Marchesani syndrome 2, dominant Geleophysic dysplasia 2 Progeroid and marfanoid aspect-lipodystrophy syndrome
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002811496.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Jan 18, 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: SCV000233950.12
First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Introduces a new cysteine residue within a calcium-binding EGF-like domain of the FBN1 gene, which may affect disulfide bonding and is predicted to alter the structure and function of the protein; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (Collod-Beroud et al., 2003); Reported in ClinVar by several laboratories as pathogenic (ClinVar Variant ID# 16440); This variant is associated with the following publications: (PMID: 19293843, 25053872, 22772377, 19839986, 12446365, 21932315, 21895641, 11700157, 19089573, 17679947, 9452085, 24161884, 24199744, 32123317, 8040326, 34957211, 12938084, 31730815) (less)
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Pathogenic
(Oct 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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Marfan syndrome
Familial thoracic aortic aneurysm and aortic dissection
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000544955.7
First in ClinVar: Apr 04, 2013 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 122 of the FBN1 protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 122 of the FBN1 protein (p.Arg122Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with ectopia lentis and/or Marfan syndrome (PMID: 8040326, 9452085, 11700157, 12446365, 17679947, 21895641, 21932315, 22772377, 25053872). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16440). 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 FBN1 protein function. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jul 20, 2018)
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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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Blueprint Genetics
Accession: SCV000927817.1
First in ClinVar: Jul 31, 2019 Last updated: Jul 31, 2019 |
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pathogenic
(Aug 18, 2011)
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criteria provided, single submitter
Method: curation, clinical testing
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Marfan Syndrome
(autosomal dominant)
Affected status: unknown, yes
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000052385.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 07, 2022 |
Comment:
Converted during submission to Pathogenic.
Observation 1:
Number of individuals with the variant: 6
Observation 2:
Number of individuals with the variant: 1
Observation 3:
Number of individuals with the variant: 1
Observation 4:
Tissue: Blood
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Pathogenic
(Jul 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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Familial thoracic aortic aneurysm and aortic dissection
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000738914.4
First in ClinVar: Apr 14, 2018 Last updated: Nov 29, 2022 |
Comment:
The p.R122C pathogenic mutation (also known as c.364C>T), located in coding exon 4 of the FBN1 gene, results from a C to T substitution at … (more)
The p.R122C pathogenic mutation (also known as c.364C>T), located in coding exon 4 of the FBN1 gene, results from a C to T substitution at nucleotide position 364. The arginine at codon 122 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the EGF-like #02 domain. The majority of FBN1 mutations identified to date have involved the substitution or generation of cysteine residues within cbEGF domains (Vollbrandt T et al. J Biol Chem. 2004;279(31):32924-32931). This particular alteration has been detected in numerous unrelated individuals with ectopia lentis (EL) and/or Marfan syndrome (MFS) (e.g., Loeys B et al. Arch. Intern. Med. 2001;161:2447-54; Comeglio P et al. Br J Ophthalmol. 2002;86:1359-62; Jin C et al. Mol. Vis. 2007;13:1280-4; Hung CC et al. Ann. Hum. Genet. 2009;73:559-67; Li J et al. Mol. Vis. 2014;20:1017-24). In addition, this alteration has been reported to segregate with disease in three families (Ståhl-Hallengren C et al. J. Clin. Invest. 1994;94:709-13; Black C et al. Hum. Mutat. 1998;Suppl 1:S198-200; Zadeh N et al. Am. J. Med. Genet. A. 2011;155A:2661-8). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Aug 01, 1994)
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no assertion criteria provided
Method: literature only
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MARFAN SYNDROME, ATYPICAL
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000038181.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
Stahl-Hallengren et al. (1994) described an unusual mutation in the FBN1 gene in a family with several members affected with an atypical form of Marfan … (more)
Stahl-Hallengren et al. (1994) described an unusual mutation in the FBN1 gene in a family with several members affected with an atypical form of Marfan syndrome (154700). The proband was 21 years old when he was referred to a rheumatologist because of pain in the hands during motion and episodes of knee joint effusions. There were no joint deformities, no scoliosis, and no cardiac symptoms. He had had spherophakia and lens dislocation since childhood. In his family, 8 members had lens dislocation and 7 of these underwent echocardiography with particular attention to aortic root dimensions and valvular function. No sign of aortic root dilatation, mitral valve prolapse, or other kind of cardiac involvement was observed either on physical examination or on echocardiography and there was no history of sudden deaths in the family. One or several episodes of knee joint effusion with moderate pain had occurred in 5 individuals. These episodes may have been related to moderate physical activity. Physical examination did not reveal ongoing joint effusion or other signs of synovitis in any of the family members. Five of the individuals with ectopia lentis had flexion contractures of the fifth proximal interphalangeal joint, whereas none of the other family members had this. The upper segment/lower segment ratio of the affected individuals was within the range characteristic of the Marfan syndrome. Linkage analysis with an informative marker in the vicinity of the fibrillin locus on chromosome 15, namely G113, revealed a lod score of 2.4 with no recombinations between the disorder and the marker. By using an automated sequenator in the screening of specific regions of FBN1 cDNA prepared from the cultured fibroblasts of the one affected family member, Stahl-Hallengren et al. (1994) identified a C-to-T transition at nucleotide 364. This mutation substituted a cysteine for arginine-122 (R122C). The mutation was confirmed in genomic DNA of the proband by use of the solid-phase minisequencing technique. This technique was also used to establish that all affected members of the family carried the same mutation, whereas unaffected members did not have the mutation. Furthermore, none of 60 Marfan patients or 60 healthy controls analyzed was shown to carry this mutation. The fibrillin polypeptide is made up of 47 repetitive EGF-like repeats interspersed by other motifs. Most of the EGF-like motifs have calcium-binding properties; however, 3 of them located close to the amino-terminal end of the fibrillin polypeptide exhibit the characteristic 6-cysteine pattern, but lack the putative calcium-binding consensus sequence. The R122C mutation in this family occurred in the second of these 3 non-calcium-binding EGF-like motifs and resulted in an extra cysteine just before the conserved second cysteine in this motif. Stevenson et al. (1982) gave the clinical description of 2 families with ectopia lentis in association with dolichostenomelia and joint stiffness. (less)
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Likely pathogenic
(Nov 07, 2017)
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no assertion criteria provided
Method: clinical testing
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Marfan syndrome
Affected status: yes
Allele origin:
germline
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Center for Medical Genetics Ghent, University of Ghent
Accession: SCV000786986.1
First in ClinVar: Jul 21, 2018 Last updated: Jul 21, 2018 |
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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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Mutation survey of candidate genes in 40 Chinese patients with congenital ectopia lentis. | Li J | Molecular vision | 2014 | PMID: 25053872 |
Detection of 15 novel mutations in 52 children from 40 families with the Marfan or Loeys-Dietz syndrome and phenotype-genotype correlations. | Pees C | Clinical genetics | 2014 | PMID: 24199744 |
Relation between genotype and left-ventricular dilatation in patients with Marfan syndrome. | Aalberts JJ | Gene | 2014 | PMID: 24161884 |
Exon 47 skipping of fibrillin-1 leads preferentially to cardiovascular defects in patients with thoracic aortic aneurysms and dissections. | Wang WJ | Journal of molecular medicine (Berlin, Germany) | 2013 | PMID: 22772377 |
Systematic screening of FBN1 gene unclassified missense variants for splice abnormalities. | Robinson DO | Clinical genetics | 2012 | PMID: 21895641 |
Ectopia lentis as the presenting and primary feature in Marfan syndrome. | Zadeh N | American journal of medical genetics. Part A | 2011 | PMID: 21932315 |
Mutation spectrum of the fibrillin-1 (FBN1) gene in Taiwanese patients with Marfan syndrome. | Hung CC | Annals of human genetics | 2009 | PMID: 19839986 |
Identification of fibrillin-1 gene mutations in Marfan syndrome by high-resolution melting analysis. | Hung CC | Analytical biochemistry | 2009 | PMID: 19328768 |
Identification of the minimal combination of clinical features in probands for efficient mutation detection in the FBN1 gene. | Stheneur C | European journal of human genetics : EJHG | 2009 | PMID: 19293843 |
Correlation of the recurrent FBN1 mutation (c.364C>T) with a unique phenotype in a Chinese patient with Marfan syndrome. | Jin C | Japanese journal of ophthalmology | 2008 | PMID: 19089573 |
Late-onset bilateral lens dislocation and glaucoma associated with a novel mutation in FBN1. | Deng T | Molecular vision | 2008 | PMID: 18615205 |
Is ectopia lentis in some cases a mild phenotypic expression of Marfan syndrome? Need for a long-term follow-up. | Pepe G | Molecular vision | 2007 | PMID: 18087243 |
Novel FBN1 mutations associated with predominant ectopia lentis and marfanoid habitus in Chinese patients. | Jin C | Molecular vision | 2007 | PMID: 17679947 |
The importance of mutation detection in Marfan syndrome and Marfan-related disorders: report of 193 FBN1 mutations. | Comeglio P | Human mutation | 2007 | PMID: 17657824 |
Juvenile bilateral lens dislocation and glaucoma associated with a novel mutation in the fibrillin 1 gene. | Challa P | Molecular vision | 2006 | PMID: 16971892 |
Comprehensive molecular screening of the FBN1 gene favors locus homogeneity of classical Marfan syndrome. | Loeys B | Human mutation | 2004 | PMID: 15241795 |
Ectopia lentis phenotypes and the FBN1 gene. | Adès LC | American journal of medical genetics. Part A | 2004 | PMID: 15054843 |
Update of the UMD-FBN1 mutation database and creation of an FBN1 polymorphism database. | Collod-Béroud G | Human mutation | 2003 | PMID: 12938084 |
Identification of FBN1 gene mutations in patients with ectopia lentis and marfanoid habitus. | Comeglio P | The British journal of ophthalmology | 2002 | PMID: 12446365 |
Mutations of FBN1 and genotype-phenotype correlations in Marfan syndrome and related fibrillinopathies. | Robinson PN | Human mutation | 2002 | PMID: 12203987 |
Sensitivity of conformation sensitive gel electrophoresis in detecting mutations in Marfan syndrome and related conditions. | Körkkö J | Journal of medical genetics | 2002 | PMID: 11826022 |
Genotype and phenotype analysis of 171 patients referred for molecular study of the fibrillin-1 gene FBN1 because of suspected Marfan syndrome. | Loeys B | Archives of internal medicine | 2001 | PMID: 11700157 |
Marfan syndrome and fibrillin disorders. | Le Parc JM | Joint bone spine | 2000 | PMID: 11143906 |
The molecular genetics of Marfan syndrome and related microfibrillopathies. | Robinson PN | Journal of medical genetics | 2000 | PMID: 10633129 |
Correlation of a recurrent FBN1 mutation (R122C) with an atypical familial Marfan syndrome phenotype. | Black C | Human mutation | 1998 | PMID: 9452085 |
Marfan Database (third edition): new mutations and new routines for the software. | Collod-Béroud G | Nucleic acids research | 1998 | PMID: 9399842 |
Fibrillin-1 mutations in Marfan syndrome and other type-1 fibrillinopathies. | Hayward C | Human mutation | 1997 | PMID: 9401003 |
Fibrillln mutations in Marfan syndrome and related phenotypes. | Ramirez F | Current opinion in genetics & development | 1996 | PMID: 8791520 |
Mutations in the human gene for fibrillin-1 (FBN1) in the Marfan syndrome and related disorders. | Dietz HC | Human molecular genetics | 1995 | PMID: 8541880 |
An extra cysteine in one of the non-calcium-binding epidermal growth factor-like motifs of the FBN1 polypeptide is connected to a novel variant of Marfan syndrome. | Ståhl-Hallengren C | The Journal of clinical investigation | 1994 | PMID: 8040326 |
Stevenson, R. E., Schroer, R. J., Taylor, H. A., Compton, J. D., Livingston, R. E., III Dislocated lens, dolichostenomelia, and joint stiffness. Proc. Greenwood Genet. Center 1: 16-22, 1982. | - | - | - | - |
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Text-mined citations for rs137854467 ...
HelpRecord last updated Apr 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.