ClinVar Genomic variation as it relates to human health
NM_003242.6(TGFBR2):c.1379G>A (p.Arg460His)
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_003242.6(TGFBR2):c.1379G>A (p.Arg460His)
Variation ID: 12515 Accession: VCV000012515.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p24.1 3: 30674229 (GRCh38) [ NCBI UCSC ] 3: 30715721 (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 22, 2016 Feb 14, 2024 Oct 30, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003242.6:c.1379G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003233.4:p.Arg460His missense NM_001024847.3:c.1454G>A NP_001020018.1:p.Arg485His missense NM_001407126.1:c.1562G>A NP_001394055.1:p.Arg521His missense NM_001407127.1:c.1487G>A NP_001394056.1:p.Arg496His missense NM_001407128.1:c.1406G>A NP_001394057.1:p.Arg469His missense NM_001407129.1:c.1382G>A NP_001394058.1:p.Arg461His missense NM_001407130.1:c.1379G>A NP_001394059.1:p.Arg460His missense NM_001407132.1:c.1274G>A NP_001394061.1:p.Arg425His missense NM_001407133.1:c.1274G>A NP_001394062.1:p.Arg425His missense NM_001407134.1:c.1274G>A NP_001394063.1:p.Arg425His missense NM_001407135.1:c.1274G>A NP_001394064.1:p.Arg425His missense NM_001407136.1:c.1274G>A NP_001394065.1:p.Arg425His missense NM_001407137.1:c.1094G>A NP_001394066.1:p.Arg365His missense NM_001407138.1:c.1019G>A NP_001394067.1:p.Arg340His missense NC_000003.12:g.30674229G>A NC_000003.11:g.30715721G>A NG_007490.1:g.72728G>A LRG_779:g.72728G>A LRG_779t1:c.1454G>A LRG_779p1:p.Arg485His LRG_779t2:c.1379G>A LRG_779p2:p.Arg460His P37173:p.Arg460His - Protein change
- R460H, R485H, R365H, R425H, R461H, R469H, R340H, R496H, R521H
- Other names
- p.R460H:CGC>CAC
- Canonical SPDI
- NC_000003.12:30674228: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
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00000
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
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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TGFBR2 | Some evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1131 | 1156 |
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
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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 (3) |
criteria provided, single submitter
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Jun 17, 2019 | RCV000013340.28 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 9, 2017 | RCV000196002.4 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Oct 30, 2023 | RCV000702388.11 |
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
(Jan 09, 2017)
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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: SCV000250947.13
First in ClinVar: Oct 11, 2015 Last updated: Mar 08, 2017 |
Comment:
The R460H mutation in the TGFBR2 gene has been reported multiple times in association with Marfan syndrome, TAAD, and related disorders (Pannu H et al., … (more)
The R460H mutation in the TGFBR2 gene has been reported multiple times in association with Marfan syndrome, TAAD, and related disorders (Pannu H et al., 2005; Disabella E et al., 2006; Law C et al., 2006). Pannu et al. identified R460H in two unrelated families and found this mutation co-segregated with a TAAD phenotype with reduced penetrance. Disabella et al. reported R460H in a 24 year-old female with aortic root dilation who met Ghent criteria for Marfan syndrome. She had a family history of sudden death in her father and paternal aunt (ages 37 and 45, respectively) due to aortic root dissection. Law et al. observed the R460H mutation in one large family with TAAD and a family history of sudden death. Postmortem autopsy on six individuals in this family identified ruptured aortic aneurysm and dissection as the cause of death. Furthermore, R460H was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Mutations at this residue (R460C, R460L) and in nearby residues (M457K, C461Y) have been reported in association with TAAD and other related disorders, supporting the functional importance of this residue and this region of the protein. Moreover, Pannu et al., suggests the R460 residue to be a mutation hot spot" for familial TAAD. Functional studies reported R460H exhibits a dominant-negative effect on extracellular signal-regulated kinase (ERK) and SMAD signaling which leads to a defect in TGF-B signaling (Horbelt D et al., 2010). In summary, R460H in the TGFBR2 gene is interpreted as a disease-causing mutation." (less)
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Pathogenic
(Oct 30, 2023)
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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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Invitae
Accession: SCV000831240.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 460 of the TGFBR2 protein (p.Arg460His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 460 of the TGFBR2 protein (p.Arg460His). This variant is present in population databases (rs104893816, gnomAD 0.004%). This missense change has been observed in individuals with TGFBR2-related conditions (PMID: 16027248, 16885183, 18852674, 23884466, 25644172, 27508510). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12515). 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 TGFBR2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects TGFBR2 function (PMID: 21098638). This variant disrupts the p.Arg460 amino acid residue in TGFBR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16027248, 16799921, 19542084, 21098638, 21267002; Invitae). 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
(Jun 17, 2019)
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criteria provided, single submitter
Method: clinical testing
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Loeys-Dietz syndrome 2
Affected status: unknown
Allele origin:
germline
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Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV001434870.1
First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
Comment:
The c.1454G>A (p.Arg485His) variant in the TGFBR2 gene has been reported in multiple unrelated families affected with Thoracic Aortic Aneurysm and Dissection (PMID 16027248,16251899, 16885183, … (more)
The c.1454G>A (p.Arg485His) variant in the TGFBR2 gene has been reported in multiple unrelated families affected with Thoracic Aortic Aneurysm and Dissection (PMID 16027248,16251899, 16885183, 25644172) and segregates with disease in some of the families (PMID 16027248, 16885183). In vitro analysis showed this variant results in severely compromised internalization of the TGF-beta RII protein (PMID 21098638). Multiple in silico algorithms predicted this p.Arg485His change to be deleterious. Therefore, this c.1454G>A (p.Arg485His) variant in the TGFBR2 gene is classified as pathogenic. (less)
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Pathogenic
(Jul 08, 2020)
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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: SCV002698236.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.R460H variant (also known as c.1379G>A), located in coding exon 5 of the TGFBR2 gene, results from a G to A substitution at nucleotide … (more)
The p.R460H variant (also known as c.1379G>A), located in coding exon 5 of the TGFBR2 gene, results from a G to A substitution at nucleotide position 1379. The arginine at codon 460 is replaced by histidine, an amino acid with highly similar properties. This variant has been found to segregate in multiple multigenerational families with syndromic and non-syndromic thoracic aortic aneurysm and dissection (TAAD) (Michaowska A et al. Pol Arch Internal Med, 2020 May; Pannu H et al. Circulation, 2005 Jul;112:513-20; Law C et al. J. Med. Genet., 2006 Dec;43:908-16). It has also been reported in several individuals with TAAD (Loeys BL et al. N. Engl. J. Med., 2006 Aug;355:788-98; Jawaid Y et al. Case Rep Cardiol, 2018 Dec;2018:8014820; Li J et al. Sci China Life Sci, 2019 Dec;62:1630-1637; Campens L et al. Orphanet J Rare Dis, 2015 Feb;10:9; Disabella E et al. Eur. J. Hum. Genet., 2006 Jan;14:34-8). Experimental studies indicate that this alteration affects TGFBR2 protein internalization and decreases TGFBR2 expression and signaling activity (Horbelt D et al. J. Cell. Sci., 2010 Dec;123:4340-50; Inamoto S et al. Cardiovasc. Res., 2010 Dec;88:520-9). Other alterations affecting the same amino acid position, p.R460C (c.1378C>T) and p.R460L (c.1379G>T), have been reported in association with TAAD (Pannu H et al. Circulation, 2005 Jul;112:513-20, Singh KK et al. Hum. Mutat., 2006 Aug;27:770-7; Horbelt D et al. J. Cell. Sci., 2010 Dec;123:4340-50; Inamoto S et al. Cardiovasc. Res., 2010 Dec;88:520-9; Tran-Fadulu V et al. J. Med. Genet., 2009 Sep;46:607-13; Barnett CP et al. Eur. J. Hum. Genet., 2011 Jun;19:624-33). 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
(Jan 17, 2023)
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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: SCV001333527.2
First in ClinVar: May 31, 2020 Last updated: Feb 04, 2024 |
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Pathogenic
(Dec 01, 2006)
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no assertion criteria provided
Method: literature only
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LOEYS-DIETZ SYNDROME 2
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000033587.4
First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2016 |
Comment on evidence:
In 2 large kindreds with autosomal dominant thoracic aortic aneurysm and dissection (LDS2; 610168), Pannu et al. (2005) found a mutation in exon 5 of … (more)
In 2 large kindreds with autosomal dominant thoracic aortic aneurysm and dissection (LDS2; 610168), Pannu et al. (2005) found a mutation in exon 5 of the TGFBR2 gene, 1379G-A, changing arginine-460 to histidine (R460H). The proband of 1 family presented with type B aortic dissection at the age of 43 years. Some affected individuals in this family also had carotid and cerebral aneurysms and dissections, as well as pulmonary artery enlargement. The proband of the second family presented at age 42 years with a type A aortic dissection that was surgically repaired. In the first family, affected individuals presented with aneurysms of both the ascending and descending thoracic aorta; in the second family, the majority of individuals presented with aneurysm of the ascending thoracic aorta. Disabella et al. (2006) identified a heterozygous R460H mutation in a 24-year-old woman with a phenotype they identified as Marfan syndrome. An affected father and aunt died of aortic root dissection at age 37 and 45 years, respectively. Law et al. (2006) described the clinical findings and natural history of 22 carriers of the R460H mutation in TGFBR2 gene in a 5-generation kindred ascertained by familial aortic dissection. There had been 8 sudden deaths; the cause of death was aortic dissection in all 6 cases in which a postmortem examination was performed. Three individuals had undergone aortic replacement surgery. Dissection had occurred throughout the aorta, and in 1 case in the absence of aortic root dilatation. Subarachnoid hemorrhage due to a ruptured berry aneurysm had occurred in 2 individuals. Four gene carriers and 1 deceased family member who were investigated had tortuous cerebral blood vessels. One had tortuous vertebral arteries, 2 had tortuous carotid arteries, and 1 had tortuous abdominal aorta. Two individuals were found to have a brachiocephalic artery aneurysm and a subclavian artery aneurysm, respectively. Despite the predisposition to aortic dilatation and dissection, members of the family did not frequently manifest the skeletal features of Marfan syndrome, with the exception of joint hypermobility. None had ocular lens dislocation. Striae and hernias were common. There was some overlap with Ehlers-Danlos syndrome type IV (130050), with soft translucent skin that was easily bruised. (less)
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Pathogenic
(Jun 05, 2018)
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no assertion criteria provided
Method: clinical testing
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Loeys-Dietz syndrome 2
Affected status: yes
Allele origin:
germline
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Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City
Accession: SCV000854709.1
First in ClinVar: Aug 22, 2016 Last updated: Aug 22, 2016 |
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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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Intrafamilial variability of cardiovascular abnormalities associated with the p.R460H mutation of the TGFBR2 gene. | Michałowska A | Polish archives of internal medicine | 2020 | PMID: 32420711 |
Application of next-generation sequencing to screen for pathogenic mutations in 123 unrelated Chinese patients with Marfan syndrome or a related disease. | Li J | Science China. Life sciences | 2019 | PMID: 31098894 |
Loeys-Dietz Syndrome Complicated by Right Coronary Artery Pseudoaneurysm. | Jawaid Y | Case reports in cardiology | 2018 | PMID: 30675401 |
Increased Prevalence of Inflammatory Bowel Disease in Patients with Mutations in Genes Encoding the Receptor Subunits for TGFβ. | Guerrerio AL | Inflammatory bowel diseases | 2016 | PMID: 27508510 |
Gene panel sequencing in heritable thoracic aortic disorders and related entities - results of comprehensive testing in a cohort of 264 patients. | Campens L | Orphanet journal of rare diseases | 2015 | PMID: 25644172 |
TGFβ receptor mutations impose a strong predisposition for human allergic disease. | Frischmeyer-Guerrerio PA | Science translational medicine | 2013 | PMID: 23884466 |
Dexamethasone normalizes aberrant elastic fiber production and collagen 1 secretion by Loeys-Dietz syndrome fibroblasts: a possible treatment? | Barnett CP | European journal of human genetics : EJHG | 2011 | PMID: 21267002 |
Quantitative analysis of TGFBR2 mutations in Marfan-syndrome-related disorders suggests a correlation between phenotypic severity and Smad signaling activity. | Horbelt D | Journal of cell science | 2010 | PMID: 21098638 |
TGFBR2 mutations alter smooth muscle cell phenotype and predispose to thoracic aortic aneurysms and dissections. | Inamoto S | Cardiovascular research | 2010 | PMID: 20628007 |
Analysis of multigenerational families with thoracic aortic aneurysms and dissections due to TGFBR1 or TGFBR2 mutations. | Tran-Fadulu V | Journal of medical genetics | 2009 | PMID: 19542084 |
Histopathologic findings in ascending aortas from individuals with Loeys-Dietz syndrome (LDS). | Maleszewski JJ | The American journal of surgical pathology | 2009 | PMID: 18852674 |
Aneurysm syndromes caused by mutations in the TGF-beta receptor. | Loeys BL | The New England journal of medicine | 2006 | PMID: 16928994 |
Clinical features in a family with an R460H mutation in transforming growth factor beta receptor 2 gene. | Law C | Journal of medical genetics | 2006 | PMID: 16885183 |
TGFBR1 and TGFBR2 mutations in patients with features of Marfan syndrome and Loeys-Dietz syndrome. | Singh KK | Human mutation | 2006 | PMID: 16799921 |
Two novel and one known mutation of the TGFBR2 gene in Marfan syndrome not associated with FBN1 gene defects. | Disabella E | European journal of human genetics : EJHG | 2006 | PMID: 16251899 |
Mutations in transforming growth factor-beta receptor type II cause familial thoracic aortic aneurysms and dissections. | Pannu H | Circulation | 2005 | PMID: 16027248 |
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Text-mined citations for rs104893816 ...
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.