ClinVar Genomic variation as it relates to human health
NM_000138.5(FBN1):c.7712G>A (p.Cys2571Tyr)
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.7712G>A (p.Cys2571Tyr)
Variation ID: 549422 Accession: VCV000549422.5
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q21.1 15: 48420794 (GRCh38) [ NCBI UCSC ] 15: 48712991 (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 Jul 21, 2018 Apr 20, 2024 Oct 1, 2021 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000138.5:c.7712G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000129.3:p.Cys2571Tyr missense NC_000015.10:g.48420794C>T NC_000015.9:g.48712991C>T NG_008805.2:g.229995G>A LRG_778:g.229995G>A LRG_778t1:c.7712G>A LRG_778p1:p.Cys2571Tyr - Protein change
- C2571Y
- Other names
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- Canonical SPDI
- NC_000015.10:48420793: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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- 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 | ||
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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 |
7467 | 7798 |
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
Help
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/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Oct 1, 2021 | RCV000663970.4 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Sep 24, 2014 | RCV001269524.2 |
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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Likely pathogenic
(Sep 24, 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: SCV001449569.1
First in ClinVar: Dec 11, 2020 Last updated: Dec 11, 2020 |
Number of individuals with the variant: 1
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Pathogenic
(Oct 01, 2021)
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criteria provided, single submitter
Method: clinical testing
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Marfan syndrome
Affected status: yes
Allele origin:
unknown
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Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV001976992.1
First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
Comment:
PM1, PM2, PM5, PP2, PP3, PP4, PP5
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Pathogenic
(Oct 19, 2020)
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criteria provided, single submitter
Method: clinical testing
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Marfan syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002767884.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with Marfan syndrome (MIM#154700). Loss of function can be caused by variants that result in premature termination codons and missense variants, whereas dominant negative are most commonly associated with missense variants (PMID: 28596305). The exact genotype-phenotype correlation for this gene is still unclear. However, patients with premature termination variants frequently presented with more systemic features of Marfan syndrome and most also suffered aortic event. Marfan syndrome patients with missense variants presented a higher prevalence of ectopia lentis. (PMID: 29357934) (I) 0107 - This gene is associated with autosomal dominant disease. Patients with an autosomal recessive form of Marfan syndrome have also been reported but are very rare (OMIM, PMID: 30485715). (I) 0115 - Variants in this gene are known to have variable expressivity. Variants in this gene are associated with several allelic disorders, and different phenotypes have been associated with the same variants (OMIM, PMID: 20301510). (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 is located in the well-established functional calcium-binding EGF-like 45 domain (PDB). Missense variants impacting a cysteine residue in a calcium-binding EGF-like domain in the FBN1 protein are likely to impact protein function (PMID: 31227806). (SP) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. The p.Cys2571Arg, p.Cys2571Phe and p.Cys2571Trp variants have been reported in patients with Marfan syndrome (ClinVar, PMIDs: 16222657, 26133393, 30293248). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. It has been reported in patients with Marfan syndrome with or without ectopia lentis (ClinVar, PMIDs: 27724990, 28588436). (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) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Likely Pathogenic
(Aug 24, 2020)
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criteria provided, single submitter
Method: clinical testing
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Marfan syndrome
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004848462.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Cys2571Tyr variant in FBN1 has been identified in 2 individuals with Marfan syndrome and was identified as a germline mosaic variant in an unafffected … (more)
The p.Cys2571Tyr variant in FBN1 has been identified in 2 individuals with Marfan syndrome and was identified as a germline mosaic variant in an unafffected parent (Zhurayev 2016 PubMed: 27724990; Martínez-Quintana 2017 PubMed: 28588436). This variant was absent from large population studies and is reported in ClinVar (allele ID: 539523). Three additional variants involving this codon (p.Cys2571Arg, p.Cys2571Trp and p.Cys2571Phe) have been identified in individuals with Marfan syndrome (Arbustini 2005 PMID: 16222657; Yang 2016 PMID: 27611364; Nair 2018 PMID: 30293248). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Furthermore, this variant affects a highly conserved cysteine residue in the EGF-like domains, which is a common finding in individuals with Marfan syndrome (Schrijver 1999). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Marfan syndrome. ACMG/AMP Criteria applied: PM1; PM2; PM5; PP3; PS4_Supporting. (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: SCV000787350.1
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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FBN1-Related Marfan Syndrome. | Adam MP | - | 2022 | PMID: 20301510 |
Phenotype-driven variant filtration strategy in exome sequencing toward a high diagnostic yield and identification of 85 novel variants in 400 patients with rare Mendelian disorders. | Marinakis NM | American journal of medical genetics. Part A | 2021 | PMID: 34008892 |
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 |
Autosomal dominant Marfan syndrome caused by a previously reported recessive FBN1 variant. | Overwater E | Molecular genetics & genomic medicine | 2019 | PMID: 30485715 |
Contribution of next generation sequencing in pediatric practice in Lebanon. A Study on 213 cases. | Nair P | Molecular genetics & genomic medicine | 2018 | PMID: 30293248 |
The importance of genotype-phenotype correlation in the clinical management of Marfan syndrome. | Becerra-Muñoz VM | Orphanet journal of rare diseases | 2018 | PMID: 29357934 |
Genotype-phenotype correlations in Marfan syndrome. | Landis BJ | Heart (British Cardiac Society) | 2017 | PMID: 28596305 |
Novel Marfan Syndrome-Associated Mutation in the FBN1 Gene Caused by Parental Mosaicism and Leading to Abnormal Limb Patterning. | Martínez-Quintana E | Molecular syndromology | 2017 | PMID: 28588436 |
Identification of FBN1 gene mutations in Ukrainian Marfan syndrome patients. | Zhurayev R | Genetics research | 2016 | PMID: 27724990 |
Aortic dilation, genetic testing, and associated diagnoses. | Zarate YA | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26133393 |
Identification of sixty-two novel and twelve known FBN1 mutations in eighty-one unrelated probands with Marfan syndrome and other fibrillinopathies. | Arbustini E | Human mutation | 2005 | PMID: 16222657 |
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Text-mined citations for rs1555394153 ...
HelpRecord last updated May 08, 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.