ClinVar Genomic variation as it relates to human health
NM_004612.4(TGFBR1):c.722C>T (p.Ser241Leu)
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_004612.4(TGFBR1):c.722C>T (p.Ser241Leu)
Variation ID: 12524 Accession: VCV000012524.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9q22.33 9: 99138006 (GRCh38) [ NCBI UCSC ] 9: 101900288 (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 May 15, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004612.4:c.722C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004603.1:p.Ser241Leu missense NM_001130916.3:c.491C>T NP_001124388.1:p.Ser164Leu missense NM_001306210.2:c.734C>T NP_001293139.1:p.Ser245Leu missense NC_000009.12:g.99138006C>T NC_000009.11:g.101900288C>T NG_007461.1:g.37877C>T P36897:p.Ser241Leu - Protein change
- S241L, S164L, S245L
- Other names
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- Canonical SPDI
- NC_000009.12:99138005:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- variation affecting protein function Variation Ontology [VariO:0003]
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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
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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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TGFBR1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
920 | 997 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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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Likely pathogenic (2) |
criteria provided, single submitter
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Oct 5, 2022 | RCV000013350.26 | |
Pathogenic (1) |
no assertion criteria provided
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Apr 3, 2015 | RCV000030540.1 | |
Pathogenic (1) |
criteria provided, single submitter
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May 15, 2023 | RCV000244262.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 4, 2018 | RCV000442105.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Sep 21, 2015 | RCV000617152.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 28, 2019 | RCV000845292.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 24, 2022 | RCV003224094.1 |
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
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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
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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
(Apr 04, 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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GeneDx
Accession: SCV000521077.4
First in ClinVar: Mar 08, 2017 Last updated: Apr 17, 2019 |
Comment:
The S241L pathogenic variant in the TGFBR1 gene has been reported in multiple individuals with a diagnosis of Loeys-Dietz syndrome and was identified as a … (more)
The S241L pathogenic variant in the TGFBR1 gene has been reported in multiple individuals with a diagnosis of Loeys-Dietz syndrome and was identified as a de novo variant in at least four cases (Mátyás et al., 2006; Adès et al., 2006; Stheneur et al., 2008; Nishida et al., 2014; Wooderchak-Donahue et al., 2015). In addition, the S241L pathogenic variant 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. The S241L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Furthermore, this substitution is located within the protein kinase domain at a position that is conserved across species. (less)
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Likely pathogenic
(Oct 05, 2022)
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criteria provided, single submitter
Method: research
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Loeys-Dietz syndrome 1
Affected status: yes
Allele origin:
germline
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Center of Excellence for Medical Genomics, Chulalongkorn University
Accession: SCV002583254.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
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Pathogenic
(Oct 24, 2022)
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criteria provided, single submitter
Method: clinical testing
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Multiple self-healing squamous epithelioma
Loeys-Dietz syndrome 1
Affected status: unknown
Allele origin:
germline
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Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Accession: SCV003920553.1
First in ClinVar: Apr 30, 2023 Last updated: Apr 30, 2023 |
Comment:
This variant has been reported in the literature in at least 10 individuals with clinical features suggestive of, or consistent with, Loeys-Dietz syndrome (Selected publications: … (more)
This variant has been reported in the literature in at least 10 individuals with clinical features suggestive of, or consistent with, Loeys-Dietz syndrome (Selected publications: Wooderchak-Donahue 2015 PIMD: 25944730; Jani 2020 PMID: 32152251; Yang 2020 PMID: 31915033; Nayak 2021 PMID: 33436942), and was found to segregate with disease in a mildly affected parent (Woolnough 2017 PMID: 28209770). In at least two individuals, the variant was determined to be de novo (Adès 2006 PMID: 16596670). This variant is not present in large control databases but is present in ClinVar, with multiple laboratories classifying it as pathogenic or likely pathogenic (Variation ID: 12524). Functional studies in vitro and in patient-derived fibroblasts demonstrate that this variant impacts protein function (Barnett 2011 PMID: 21267002; Cardoso 2012 PMID: 22414221). Evolutionary conservation and computational prediction tools support a deleterious effect of this variant. In summary, this variant is classified as pathogenic. (less)
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Pathogenic
(Aug 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Loeys-Dietz syndrome 1
Marfan syndrome (Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
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Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations
Accession: SCV000986693.1
First in ClinVar: Sep 05, 2019 Last updated: Sep 05, 2019 |
Comment:
The p.Ser241Leu variant was found in one individual with Marfanoid phenotype at our clinical center. This variant is a known mutation associated with a Loeys-Dietz … (more)
The p.Ser241Leu variant was found in one individual with Marfanoid phenotype at our clinical center. This variant is a known mutation associated with a Loeys-Dietz syndrome (PMID: 16596670, 16791849, 16928994, 27879313) and was also found in patients with colorectal cancer (PMID: 28743916) with a functional consequences of the variant. The S241L variant has a very low frequency (rs111854391). ClinVar has an entry for this variant (Variation ID: 12524). Based on this evidences the p.Ser241Leu is classified as Pathogenic. (less)
Clinical Features:
High palate (present) , Dental crowding (present) , Myopia (present) , Pectus carinatum (present) , Kyphoscoliosis (present) , Joint hypermobility (present) , Pes planus (present) … (more)
High palate (present) , Dental crowding (present) , Myopia (present) , Pectus carinatum (present) , Kyphoscoliosis (present) , Joint hypermobility (present) , Pes planus (present) , Arachnodactyly (present) , Aortic regurgitation (present) , Aortic root aneurysm (present) , Mitral valve prolapse (present) , Abnormal cardiac ventricle morphology (present) , Tricuspid valve prolapse (present) , Dolichostenomelia (present) (less)
Age: 30-39 years
Sex: male
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Likely pathogenic
(Sep 21, 2015)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000318311.5
First in ClinVar: Oct 02, 2016 Last updated: Apr 13, 2018 |
Comment:
The p.S241L variant (also known as c.722C>T), located in coding exon 4 of the TGFBR1 gene, results from a C to T substitution at nucleotide … (more)
The p.S241L variant (also known as c.722C>T), located in coding exon 4 of the TGFBR1 gene, results from a C to T substitution at nucleotide position 722. The serine at codon 241 is replaced by leucine, an amino acid with dissimilar properties. In one study, p.S241L was detected in two unrelated patients withMarfanoidhabitusanddysmorphiccraniofacialfeatures. One patient had normal intelligence and the other had learning difficulties;craniosynostosiswas present in one patient, but both had pronouncedcraniofacialfeatures. Both patients had aortic dilatation and scoliosis. The p.S241L alteration,located in theserine-threoninekinasedomain, was not detected in the parents of either patient (de novo), the sister of one patient, or 100 control individuals(AdèsLC et al.Am J Med Genet A. 2006;140(10):1047-1058). In another study, p.S241Lwas reported in a patient born in 1971 who fulfilled the diagnostic criteria forMarfansyndrome and also had features supporting the diagnosis ofLoeys-Dietzsyndrome; family history was negative (MátyásG et al.HumMutat. 2006;27(8):760-769). It was also reported in multiple individuals affected by Loeys-Dietz syndrom(LoeysBLet al.NEnglJ Med. 2006;355(8):788-798;StheneurC et al, Hum.Mutat. 2008 Nov; 29(11):E284-95;NishidaK et al,PediatrInt 2014 Dec; 56(6):e82-5). With patient derived fibroblasts, it was shown that this variant cause decreased elastin and fibulin 1 mRNA expression, and also impaired the deposition of elastin, fibrillin 1 and fibulin 1 into elastic fibers (Barnett CP et al, Eur. J. Hum. Genet. 2011 Jun; 19(6):624-33). An in vitro study suggested the alteration negativelyaffected both the basal and TGF-beta induced Smad signaling (CardosoS et al, J.Recept. SignalTransduct. Res. 2012Jun; 32(3):150-5).This variant was previously reported in the SNPDatabase as rs111854391, butnot found in population-based cohorts in the following databases:NHLBIExomeSequencing Project (ESP) and 1000 Genomes Project.This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive.Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
Number of individuals with the variant: 1
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Pathogenic
(May 15, 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: SCV000548341.6
First in ClinVar: Oct 02, 2016 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TGFBR1 function (PMID: 22414221). Advanced modeling … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TGFBR1 function (PMID: 22414221). 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 TGFBR1 protein function. ClinVar contains an entry for this variant (Variation ID: 12524). This missense change has been observed in individual(s) with Loeys-Dietz syndrome and Furlong syndrome and aortic dissection and clinical features of Loeys-Dietz syndrome (PMID: 16596670, 16791849, 18781618, 23884466, 25521989, 25944730, 28209770). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 241 of the TGFBR1 protein (p.Ser241Leu). (less)
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Pathogenic
(Apr 03, 2015)
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no assertion criteria provided
Method: clinical testing
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Loeys-Dietz Syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000053211.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
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Pathogenic
(May 15, 2006)
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no assertion criteria provided
Method: literature only
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LOEYS-DIETZ SYNDROME 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000033597.4
First in ClinVar: Apr 04, 2013 Last updated: Sep 30, 2018 |
Comment on evidence:
In 2 patients judged to have Furlong syndrome (see LDS1, 609192), Ades et al. (2006) found an identical heterozygous missense mutation, ser241 to leu (S241L), … (more)
In 2 patients judged to have Furlong syndrome (see LDS1, 609192), Ades et al. (2006) found an identical heterozygous missense mutation, ser241 to leu (S241L), in the TGFBR1 gene. The mutation, which arose from a C-to-T transition at nucleotide position 722, alters a highly conserved nonpolar serine in the serine-threonine kinase domain to a polar leucine residue. (less)
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Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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variation affecting protein function
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Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations
Accession: SCV000986693.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Are Patients With Loeys-Dietz Syndrome Misdiagnosed With Beals Syndrome? | Woolnough R | Pediatrics | 2017 | PMID: 28209770 |
Clinical utility of a next generation sequencing panel assay for Marfan and Marfan-like syndromes featuring aortopathy. | Wooderchak-Donahue W | American journal of medical genetics. Part A | 2015 | PMID: 25944730 |
Postoperative mitral leaflet rupture in an infant with Loeys-Dietz syndrome. | Nishida K | Pediatrics international : official journal of the Japan Pediatric Society | 2014 | PMID: 25521989 |
TGFβ receptor mutations impose a strong predisposition for human allergic disease. | Frischmeyer-Guerrerio PA | Science translational medicine | 2013 | PMID: 23884466 |
TGFBR1 mutations associated with Loeys-Dietz syndrome are inactivating. | Cardoso S | Journal of receptor and signal transduction research | 2012 | PMID: 22414221 |
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 |
Identification of 23 TGFBR2 and 6 TGFBR1 gene mutations and genotype-phenotype investigations in 457 patients with Marfan syndrome type I and II, Loeys-Dietz syndrome and related disorders. | Stheneur C | Human mutation | 2008 | PMID: 18781618 |
Aneurysm syndromes caused by mutations in the TGF-beta receptor. | Loeys BL | The New England journal of medicine | 2006 | PMID: 16928994 |
Identification and in silico analyses of novel TGFBR1 and TGFBR2 mutations in Marfan syndrome-related disorders. | Mátyás G | Human mutation | 2006 | PMID: 16791849 |
FBN1, TGFBR1, and the Marfan-craniosynostosis/mental retardation disorders revisited. | Adès LC | American journal of medical genetics. Part A | 2006 | PMID: 16596670 |
Text-mined citations for rs111854391 ...
HelpRecord last updated Mar 05, 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.