The IVS-I (-1) or codon 30 (G->A) variant (HBB: c.92G>A; p.Arg31Lys, also known as Arg30Lys when numbered from the mature protein, HbVar ID: 816, rs33960103) is reported in the compound heterozygous state in individuals affected with beta (0) thalassemia (see link to HbVar, Kalaydjieva 1989, Maazoun 2016, Muniz 2000). This variant is also reported in ClinVar (Variation ID: 36337), and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant is located in the last nucleotide of exon 1 and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by severely weakening the nearby canonical donor splice site. Additionally, another variant at this nucleotide (Hb Monroe variant, c.92G>C; p.Arg31Thr, HbVar ID: 290) has been reported in individuals with beta (0) thalassemia, is shown to affect splicing, and is considered pathogenic (Vidaud 1989). Based on available information, the p.Arg31Lys variant is considered to be likely pathogenic. References: Link to HbVar for IVS-I (-1): https://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=816 Kalaydjieva L et al. The molecular basis of beta thalassaemia in Bulgaria. J Med Genet. 1989 Oct;26(10):614-8. PMID: 2577233. Maazoun F et al. Symptomatic extramedullary haematopoiesis in beta-thalassemia: A retrospective single centre study. Rev Med Interne. 2016 Jan;37(1):5-12. French. PMID: 26410419. Muniz A et al. Beta-thalassaemia in Cubans: novel allele increases the genetic diversity at the HBB locus in the Caribbean. Am J Hematol. 2000 May;64(1):7-14. PMID: 10815781. Vidaud M et al. A 5' splice-region G----C mutation in exon 1 of the human beta-globin gene inhibits pre-mRNA splicing: a mechanism for beta+-thalassemia. Proc Natl Acad Sci U S A. 1989 Feb;86(3):1041-5. PMID: 2915972.
ClinVar Genomic variation as it relates to human health
NM_000518.5(HBB):c.92G>A (p.Arg31Lys)
Germline
Classification
Help
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.
(7)
Help
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.
Pathogenic/Likely pathogenic
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000518.5(HBB):c.92G>A (p.Arg31Lys)
Variation ID: 36337 Accession: VCV000036337.21
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 11p15.4 11: 5226930 (GRCh38) [ NCBI UCSC ] 11: 5248160 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 14, 2024 Jul 18, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000518.5:c.92G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000509.1:p.Arg31Lys missense NC_000011.10:g.5226930C>T NC_000011.9:g.5248160C>T NG_000007.3:g.70686G>A NG_042296.1:g.461C>T NG_046672.1:g.4865C>T NG_059281.1:g.5142G>A LRG_1232:g.5142G>A LRG_1232t1:c.92G>A LRG_1232p1:p.Arg31Lys - Protein change
- R31K
- Other names
-
CD 30 (G>A) or IVS I (-1) AGG>AAG (Arg>Lys)
- Canonical SPDI
- NC_000011.10:5226929:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- 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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| HBB | - | - |
GRCh38 GRCh37 |
22 | 1834 | |
| LOC106099062 | - | - | - | GRCh38 | - | 862 |
| LOC107133510 | - | - | - | GRCh38 | - | 1784 |
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. |
|---|---|---|---|---|
| Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Jan 26, 2017 | RCV000030006.5 | |
| Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jul 18, 2023 | RCV000506003.18 |
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. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Jan 12, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV002506319.2
First in ClinVar: May 07, 2022 Last updated: Dec 24, 2022 |
Comment:
The IVS-I (-1) or codon 30 (G->A) variant (HBB: c.92G>A; p.Arg31Lys, also known as Arg30Lys when numbered from the mature protein, HbVar ID: 816, rs33960103) … (more)
The IVS-I (-1) or codon 30 (G->A) variant (HBB: c.92G>A; p.Arg31Lys, also known as Arg30Lys when numbered from the mature protein, HbVar ID: 816, rs33960103) is reported in the compound heterozygous state in individuals affected with beta (0) thalassemia (see link to HbVar, Kalaydjieva 1989, Maazoun 2016, Muniz 2000). This variant is also reported in ClinVar (Variation ID: 36337), and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant is located in the last nucleotide of exon 1 and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by severely weakening the nearby canonical donor splice site. Additionally, another variant at this nucleotide (Hb Monroe variant, c.92G>C; p.Arg31Thr, HbVar ID: 290) has been reported in individuals with beta (0) thalassemia, is shown to affect splicing, and is considered pathogenic (Vidaud 1989). Based on available information, the p.Arg31Lys variant is considered to be likely pathogenic. References: Link to HbVar for IVS-I (-1): https://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=816 Kalaydjieva L et al. The molecular basis of beta thalassaemia in Bulgaria. J Med Genet. 1989 Oct;26(10):614-8. PMID: 2577233. Maazoun F et al. Symptomatic extramedullary haematopoiesis in beta-thalassemia: A retrospective single centre study. Rev Med Interne. 2016 Jan;37(1):5-12. French. PMID: 26410419. Muniz A et al. Beta-thalassaemia in Cubans: novel allele increases the genetic diversity at the HBB locus in the Caribbean. Am J Hematol. 2000 May;64(1):7-14. PMID: 10815781. Vidaud M et al. A 5' splice-region G----C mutation in exon 1 of the human beta-globin gene inhibits pre-mRNA splicing: a mechanism for beta+-thalassemia. Proc Natl Acad Sci U S A. 1989 Feb;86(3):1041-5. PMID: 2915972. (less)
|
|
|
Pathogenic
(Feb 02, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000601332.5
First in ClinVar: Sep 30, 2017 Last updated: Jan 06, 2024 |
Comment:
The HBB c.92G>A (p.Arg31Lys) variant (also known as IVS-I (-1) or Codon 30 (G>A)) changes the last nucleotide of exon 1 and is located at … (more)
The HBB c.92G>A (p.Arg31Lys) variant (also known as IVS-I (-1) or Codon 30 (G>A)) changes the last nucleotide of exon 1 and is located at the exon 1-intron 1 junction. It is predicted to interfere with proper beta-globin mRNA splicing and may affect normal beta-globin mRNA production. This variant is associated with beta (0)-thalassemia (PMID: 2577233 (1989), and PMID: 19254853 (2009)). (less)
|
|
|
Likely pathogenic
(Jul 18, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001576509.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has … (more)
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the c.92G nucleotide in the HBB gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 2915972, 18056002, 27828729). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 36337). This variant is also known as p.Arg30Lys, codon 30 (G‚ÜíA) , IVS-I (-1). This missense change has been observed in individuals with beta thalassemia (PMID: 10815781, 26410419). This variant is present in population databases (rs33960103, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 31 of the HBB protein (p.Arg31Lys). This variant also falls at the last nucleotide of exon 1, which is part of the consensus splice site for this exon. (less)
|
|
|
Likely pathogenic
(Jan 26, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Beta-thalassemia HBB/LCRB
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000788510.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
|
|
|
likely pathogenic
(Aug 18, 2011)
|
criteria provided, single submitter
Method: curation, clinical testing
|
Beta Thalassemia
(autosomal recessive)
Affected status: yes, unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000052661.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 07, 2022 |
Comment:
Converted during submission to Likely pathogenic.
Observation 1:
Number of individuals with the variant: 1
Observation 2:
Tissue: Blood
Observation 3:
Tissue: Blood
|
|
|
Pathogenic
(Nov 25, 2019)
|
no assertion criteria provided
Method: curation
|
beta Thalassemia
Affected status: unknown
Allele origin:
germline
|
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics
Accession: SCV001244509.1
First in ClinVar: May 04, 2020 Last updated: May 04, 2020 |
|
|
|
Likely pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Beta thalassemia
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001453787.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
Comment:
Comment:
The HBB c.92G>A (p.Arg31Lys) variant (also known as IVS-I (-1) or Codon 30 (G>A)) changes the last nucleotide of exon 1 and is located at the exon 1-intron 1 junction. It is predicted to interfere with proper beta-globin mRNA splicing and may affect normal beta-globin mRNA production. This variant is associated with beta (0)-thalassemia (PMID: 2577233 (1989), and PMID: 19254853 (2009)).
Comment:
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the c.92G nucleotide in the HBB gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 2915972, 18056002, 27828729). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 36337). This variant is also known as p.Arg30Lys, codon 30 (G‚ÜíA) , IVS-I (-1). This missense change has been observed in individuals with beta thalassemia (PMID: 10815781, 26410419). This variant is present in population databases (rs33960103, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 31 of the HBB protein (p.Arg31Lys). This variant also falls at the last nucleotide of exon 1, which is part of the consensus splice site for this exon.
Comment:
Converted during submission to Likely pathogenic.
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. |
Comment:
The IVS-I (-1) or codon 30 (G->A) variant (HBB: c.92G>A; p.Arg31Lys, also known as Arg30Lys when numbered from the mature protein, HbVar ID: 816, rs33960103) is reported in the compound heterozygous state in individuals affected with beta (0) thalassemia (see link to HbVar, Kalaydjieva 1989, Maazoun 2016, Muniz 2000). This variant is also reported in ClinVar (Variation ID: 36337), and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant is located in the last nucleotide of exon 1 and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by severely weakening the nearby canonical donor splice site. Additionally, another variant at this nucleotide (Hb Monroe variant, c.92G>C; p.Arg31Thr, HbVar ID: 290) has been reported in individuals with beta (0) thalassemia, is shown to affect splicing, and is considered pathogenic (Vidaud 1989). Based on available information, the p.Arg31Lys variant is considered to be likely pathogenic. References: Link to HbVar for IVS-I (-1): https://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=816 Kalaydjieva L et al. The molecular basis of beta thalassaemia in Bulgaria. J Med Genet. 1989 Oct;26(10):614-8. PMID: 2577233. Maazoun F et al. Symptomatic extramedullary haematopoiesis in beta-thalassemia: A retrospective single centre study. Rev Med Interne. 2016 Jan;37(1):5-12. French. PMID: 26410419. Muniz A et al. Beta-thalassaemia in Cubans: novel allele increases the genetic diversity at the HBB locus in the Caribbean. Am J Hematol. 2000 May;64(1):7-14. PMID: 10815781. Vidaud M et al. A 5' splice-region G----C mutation in exon 1 of the human beta-globin gene inhibits pre-mRNA splicing: a mechanism for beta+-thalassemia. Proc Natl Acad Sci U S A. 1989 Feb;86(3):1041-5. PMID: 2915972.
Comment:
The HBB c.92G>A (p.Arg31Lys) variant (also known as IVS-I (-1) or Codon 30 (G>A)) changes the last nucleotide of exon 1 and is located at the exon 1-intron 1 junction. It is predicted to interfere with proper beta-globin mRNA splicing and may affect normal beta-globin mRNA production. This variant is associated with beta (0)-thalassemia (PMID: 2577233 (1989), and PMID: 19254853 (2009)).
Comment:
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the c.92G nucleotide in the HBB gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 2915972, 18056002, 27828729). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 36337). This variant is also known as p.Arg30Lys, codon 30 (G‚ÜíA) , IVS-I (-1). This missense change has been observed in individuals with beta thalassemia (PMID: 10815781, 26410419). This variant is present in population databases (rs33960103, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 31 of the HBB protein (p.Arg31Lys). This variant also falls at the last nucleotide of exon 1, which is part of the consensus splice site for this exon.
Comment:
Converted during submission to Likely pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| The phenotypic and molecular diversity of hemoglobinopathies in India: A review of 15 years at a referral center. | Nadkarni AH | International journal of laboratory hematology | 2019 | PMID: 30489691 |
| Cross-Sectional Study for the Detection of Mutations in the Beta-Globin Gene Among Patients with Hemoglobinopathies in the Bengali Population. | Panja A | Genetic testing and molecular biomarkers | 2017 | PMID: 27828729 |
| The molecular characterization of Beta globin gene in thalassemia patients reveals rare and a novel mutations in Pakistani population. | Yasmeen H | European journal of medical genetics | 2016 | PMID: 27263053 |
| [Symptomatic extramedullary haematopoiesis in β-thalassemia: A retrospective single centre study]. | Maazoun F | La Revue de medecine interne | 2016 | PMID: 26410419 |
| Genotype-phenotype correlation and report of novel mutations in β-globin gene in thalassemia patients. | Nagar R | Blood cells, molecules & diseases | 2015 | PMID: 25976460 |
| Broader spectrum of β-thalassemia mutations in Oman: regional distribution and comparison with neighboring countries. | Hassan SM | Hemoglobin | 2015 | PMID: 25677748 |
| DNA damage: beta zero versus beta plus thalassemia. | Sagar CS | Annals of human biology | 2015 | PMID: 25541274 |
| Molecular characterization of β-thalassemia in four communities in South Gujarat--codon 30 (G → A) a predominant mutation in the Kachhiya Patel community. | Bhukhanvala DS | Annals of hematology | 2013 | PMID: 23665927 |
| Hb E/β-thalassemia: the second most common cause of transfusion-dependent thalassemia in the Gwalior-Chambal region of Central India. | Kumar R | Hemoglobin | 2012 | PMID: 22738610 |
| Molecular basis of β-thalassemia in Karnataka, India. | Kulkarni GD | Genetic testing and molecular biomarkers | 2012 | PMID: 21978377 |
| Mutations of a country: a mutation review of single gene disorders in the United Arab Emirates (UAE). | Al-Gazali L | Human mutation | 2010 | PMID: 20437613 |
| Profiling β-thalassaemia mutations in India at state and regional levels: implications for genetic education, screening and counselling programmes. | Sinha S | The HUGO journal | 2009 | PMID: 21119755 |
| Impact of single nucleotide polymorphisms in HBB gene causing haemoglobinopathies: in silico analysis. | George Priya Doss C | New biotechnology | 2009 | PMID: 19429541 |
| Regional heterogeneity of beta-thalassemia mutations in the multi ethnic Indian population. | Colah R | Blood cells, molecules & diseases | 2009 | PMID: 19254853 |
| Missense mutation of the last nucleotide of exon 1 (G->C) of beta globin gene not only leads to undetectable mutant peptide and transcript but also interferes with the expression of wild allele. | Agarwal N | Haematologica | 2007 | PMID: 18056002 |
| Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
| Beta-thalassaemia in Cubans: novel allele increases the genetic diversity at the HBB locus in the Caribbean. | Muñiz A | American journal of hematology | 2000 | PMID: 10815781 |
| Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
| Rare beta-thalassaemia mutations in Asian indians. | Varawalla NY | British journal of haematology | 1991 | PMID: 1772786 |
| A 5' splice-region G----C mutation in exon 1 of the human beta-globin gene inhibits pre-mRNA splicing: a mechanism for beta+-thalassemia. | Vidaud M | Proceedings of the National Academy of Sciences of the United States of America | 1989 | PMID: 2915972 |
| The molecular basis of beta thalassaemia in Bulgaria. | Kalaydjieva L | Journal of medical genetics | 1989 | PMID: 2577233 |
| https://ithanet.eu/db/ithagenes?ithaID=99 | - | - | - | - |
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Text-mined citations for rs33960103 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 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.