ClinVar Genomic variation as it relates to human health
NM_000138.5(FBN1):c.299G>A (p.Cys100Tyr)
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.299G>A (p.Cys100Tyr)
Variation ID: 228262 Accession: VCV000228262.7
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q21.1 15: 48610775 (GRCh38) [ NCBI UCSC ] 15: 48902972 (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 May 29, 2016 Jul 23, 2024 Jun 24, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000138.5:c.299G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000129.3:p.Cys100Tyr missense NC_000015.10:g.48610775C>T NC_000015.9:g.48902972C>T NG_008805.2:g.40014G>A LRG_778:g.40014G>A LRG_778t1:c.299G>A LRG_778p1:p.Cys100Tyr - Protein change
- C100Y
- Other names
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- Canonical SPDI
- NC_000015.10:48610774:C:T
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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
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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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FBN1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
7554 | 7887 |
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
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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, multiple submitters, no conflicts
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Jun 24, 2022 | RCV000220364.7 |
Submissions - Germline
Classification
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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
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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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Likely pathogenic
(Feb 04, 2015)
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criteria provided, single submitter
Method: clinical testing
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Marfan syndrome
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000271224.2
First in ClinVar: May 29, 2016 Last updated: May 29, 2016 |
Comment:
The p.Cys100Tyr variant in FBN1 has been identified in 1 African American indivi dual with Marfan syndrome, 1 Chinese individual with Marfan syndrome, and segreg … (more)
The p.Cys100Tyr variant in FBN1 has been identified in 1 African American indivi dual with Marfan syndrome, 1 Chinese individual with Marfan syndrome, and segreg ated with disease in 1 affected relative (LMM unpublished data, Chung 2009). It was absent from large population studies. Additionally, another variant at the s ame position (p.Cys100Phe) has been identified to occur de novo in 1 Asian indiv idual with Marfan syndrome (LMM unpublished data), suggesting that a change at t his position may not be tolerated. Computational prediction tools and conservati on analysis suggest that the p.Cys100Tyr variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Furthermor e, this variant affects a highly conserved cysteine residue in the EGF-like doma ins, which is a common finding in individuals with Marfan syndrome (Schrijver 19 99). In summary, although additional studies are required to fully establish its clinical significance, the p.Cys100Tyr variant is likely pathogenic. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(Jun 24, 2022)
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criteria provided, single submitter
Method: clinical testing
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Marfan syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002557757.2
First in ClinVar: Aug 08, 2022 Last updated: Jul 23, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with FBN1-related disease. Variants predicted to result in nonsense mediated decay are commonly associated with severe Marfan syndrome (MIM#154700). Missense variants with both dominant negative and loss of function effects are associated with Marfan syndrome and ectopia lentis (MIM#129600; OMIM, PMID: 29357934). The exact genotype-phenotype correlation for this gene is still unclear, and is compounded by variable expressivity (PMID: 20301510). (I) 0107 - This gene is predominantly associated with autosomal dominant disease; autosomal recessive forms of Marfan syndrome have been reported infrequently (PMID: 27274304; 31950671). 0115 - Variants in this gene are known to have variable expressivity. The genotype-phenotype correlations for this gene are unclear, with variants reported in patients with a range of phenotypes (PMID: 20301510, OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from cysteine to tyrosine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0601 - Variant affects a well-established functional cysteine residue of an EGF-like domain. Cysteine substitutions in EGF-like domains are commonly disease-causing (PMID: 31227806). (SP) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. Alternative changes to phenylalanine and arginine have been described as pathogenic or likely pathogenic in ClinVar and the literature (PMID: 31730815). (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been reported likely pathogenic in ClinVar and in the literature in an individual with Marfan syndrome (PMID: 19533785). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1207 - Parental origin of the variant is unresolved. Mother does not have the variant. Father was not tested. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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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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FBN1-Related Marfan Syndrome. | Adam MP | - | 2022 | PMID: 20301510 |
Compound heterozygous mutations in FBN1 in a large family with Marfan syndrome. | McInerney-Leo AM | Molecular genetics & genomic medicine | 2020 | PMID: 31950671 |
Mutation analysis of the FBN1 gene in a cohort of patients with Marfan Syndrome: A 10-year single center experience. | Mannucci L | Clinica chimica acta; international journal of clinical chemistry | 2020 | PMID: 31730815 |
Variability in gene-based knowledge impacts variant classification: an analysis of FBN1 missense variants in ClinVar. | Baudhuin LM | European journal of human genetics : EJHG | 2019 | PMID: 31227806 |
The importance of genotype-phenotype correlation in the clinical management of Marfan syndrome. | Becerra-Muñoz VM | Orphanet journal of rare diseases | 2018 | PMID: 29357934 |
Marfan syndrome: current perspectives. | Pepe G | The application of clinical genetics | 2016 | PMID: 27274304 |
Identification of novel FBN1 and TGFBR2 mutations in 65 probands with Marfan syndrome or Marfan-like phenotypes. | Chung BH | American journal of medical genetics. Part A | 2009 | PMID: 19533785 |
Cysteine substitutions in epidermal growth factor-like domains of fibrillin-1: distinct effects on biochemical and clinical phenotypes. | Schrijver I | American journal of human genetics | 1999 | PMID: 10486319 |
Text-mined citations for rs397515782 ...
HelpRecord last updated Jul 23, 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.