VCV000042365.19 - ClinVar

NM_000138.5(FBN1):c.4567C>T (p.Arg1523Ter)

Germline

Classification

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.

(9)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000138.5(FBN1):c.4567C>T (p.Arg1523Ter)

Variation ID: 42365 Accession: VCV000042365.19

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 15q21.1 15: 48468427 (GRCh38) [ NCBI UCSC ] 15: 48760624 (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	Jan 31, 2015	Nov 30, 2024	Jan 13, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000138.5:c.4567C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000129.3:p.Arg1523Ter	nonsense
NC_000015.10:g.48468427G>A
NC_000015.9:g.48760624G>A
NG_008805.2:g.182362C>T
LRG_778:g.182362C>T
LRG_778t1:c.4567C>T	LRG_778p1:p.Arg1523Ter

... more HGVS ... less HGVS

Protein change

R1523*

Other names

Canonical SPDI

NC_000015.10:48468426:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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

ClinGen: CA015204 dbSNP: rs397515812 VarSome

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
Gene	OMIM	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.
FBN1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	7744	8084

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.
Marfan syndrome	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Apr 20, 2018	RCV000035205.7
not provided	Pathogenic (1)	criteria provided, single submitter	Jan 17, 2023	RCV000579083.3
Familial thoracic aortic aneurysm and aortic dissection Marfan syndrome	Pathogenic (1)	criteria provided, single submitter	Jan 13, 2024	RCV000539432.7
Familial thoracic aortic aneurysm and aortic dissection	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Dec 16, 2020	RCV000770665.5
Isolated thoracic aortic aneurysm	Likely pathogenic (1)	criteria provided, single submitter	Sep 1, 2018	RCV001374850.1

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 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.
Pathogenic (Apr 20, 2018)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Marfan syndrome (Autosomal dominant inheritance) Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000058848.5 First in ClinVar: May 03, 2013 Last updated: Jan 31, 2015	Publications: PubMed (5) PubMed: 12068374‚ 23505274‚ 10874320‚ 19159394‚ 25101912 Comment: The p.Arg1523X variant in FBN1 has been reported in at least 6 individuals with clinical features of Marfan syndrome (Vandersteen 2013, Schrijver 2002, Baudhuin 2014, … (more) The p.Arg1523X variant in FBN1 has been reported in at least 6 individuals with clinical features of Marfan syndrome (Vandersteen 2013, Schrijver 2002, Baudhuin 2014, Soylen 2009, Youil 2000, LMM data) and has also been reported by other cl inical laboratories in ClinVar (Variation ID: 42365). It has been identified in 1/245856 chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.b roadinstitute.org; dbSNP rs397515812). This nonsense variant leads to a prematur e termination codon at position 1523, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the FBN1 gene is an establis hed disease mechanism in individuals with Marfan syndrome. In summary, this vari ant meets criteria to be classified as pathogenic for Marfan syndrome in an auto somal dominant manner based upon presence in multiple affected individuals and t he predicted impact on the protein. ACMG/AMP Criteria applied: PVS1, PS4. (less) Number of individuals with the variant: 2
Pathogenic (Jan 17, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000680640.3 First in ClinVar: Feb 13, 2018 Last updated: Feb 07, 2023	Comment: Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene … (more) Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 10874320, 25525159, 12068374, 31279664, 31447099, 23505274, 19159394, 31325479, 31730815, 34498425, 35943490, 19012347, 25101912, 33824467) (less)
Pathogenic (Nov 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Marfan syndrome Affected status: yes Allele origin: germline	Center for Human Genetics, Inc, Center for Human Genetics, Inc Accession: SCV000781374.1 First in ClinVar: Jan 31, 2015 Last updated: Jan 31, 2015
Likely pathogenic (Sep 01, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Isolated thoracic aortic aneurysm Affected status: yes Allele origin: germline	Department of Vascular Biology, Beijing Anzhen Hospital Accession: SCV001439534.1 First in ClinVar: Apr 28, 2021 Last updated: Apr 28, 2021	Sex: mixed
Pathogenic (May 27, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial thoracic aortic aneurysm and aortic dissection Affected status: unknown Allele origin: germline	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Study: Canadian Open Genetics Repository Accession: SCV000902124.2 First in ClinVar: May 06, 2019 Last updated: Dec 29, 2021
Pathogenic (Jan 13, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Marfan syndrome Familial thoracic aortic aneurysm and aortic dissection Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000627921.4 First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024	Publications: PubMed (4) PubMed: 17657824‚ 19293843‚ 10874320‚ 12068374 Comment: This sequence change creates a premature translational stop signal (p.Arg1523) in the FBN1 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Arg1523) in the FBN1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FBN1 are known to be pathogenic (PMID: 17657824, 19293843). This variant is present in population databases (rs397515812, gnomAD no frequency). This premature translational stop signal has been observed in individuals with Marfan syndrome (PMID: 10874320, 12068374). ClinVar contains an entry for this variant (Variation ID: 42365). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Dec 16, 2020)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Familial thoracic aortic aneurysm and aortic dissection Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002637287.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (4) PubMed: 10874320‚ 12068374‚ 19012347‚ 19159394 Comment: The p.R1523* pathogenic mutation (also known as c.4567C>T), located in coding exon 36 of the FBN1 gene, results from a C to T substitution at … (more) The p.R1523* pathogenic mutation (also known as c.4567C>T), located in coding exon 36 of the FBN1 gene, results from a C to T substitution at nucleotide position 4567. This changes the amino acid from an arginine to a stop codon within coding exon 36. THis alteration has been reported in subjects with features of Marfan syndrome and has been reported as de novo (Youil R et al. Hum Mutat, 2000 Jul;16:92-3; Schrijver I et al. Am J Hum Genet, 2002 Aug;71:223-37; Rybczynski M et al. Am J Med Genet A, 2008 Dec;146A:3157-66; Söylen B et al. Clin Genet, 2009 Mar;75:265-70). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Marfan syndrome Affected status: yes Allele origin: germline	Juno Genomics, Hangzhou Juno Genomics, Inc Accession: SCV005418369.1 First in ClinVar: Nov 30, 2024 Last updated: Nov 30, 2024	Comment: PVS1+PM2_Supporting+PS4+PM6
Pathogenic (Nov 07, 2017)	no assertion criteria provided Method: clinical testing	Marfan syndrome Affected status: yes Allele origin: germline	Center for Medical Genetics Ghent, University of Ghent Accession: SCV000787077.1 First in ClinVar: Jul 21, 2018 Last updated: Jul 21, 2018

Comment:

The p.Arg1523X variant in FBN1 has been reported in at least 6 individuals with clinical features of Marfan syndrome (Vandersteen 2013, Schrijver 2002, Baudhuin 2014, Soylen 2009, Youil 2000, LMM data) and has also been reported by other cl inical laboratories in ClinVar (Variation ID: 42365). It has been identified in 1/245856 chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.b roadinstitute.org; dbSNP rs397515812). This nonsense variant leads to a prematur e termination codon at position 1523, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the FBN1 gene is an establis hed disease mechanism in individuals with Marfan syndrome. In summary, this vari ant meets criteria to be classified as pathogenic for Marfan syndrome in an auto somal dominant manner based upon presence in multiple affected individuals and t he predicted impact on the protein. ACMG/AMP Criteria applied: PVS1, PS4.

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 10874320, 25525159, 12068374, 31279664, 31447099, 23505274, 19159394, 31325479, 31730815, 34498425, 35943490, 19012347, 25101912, 33824467)

Comment:

This sequence change creates a premature translational stop signal (p.Arg1523*) in the FBN1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FBN1 are known to be pathogenic (PMID: 17657824, 19293843). This variant is present in population databases (rs397515812, gnomAD no frequency). This premature translational stop signal has been observed in individuals with Marfan syndrome (PMID: 10874320, 12068374). ClinVar contains an entry for this variant (Variation ID: 42365). For these reasons, this variant has been classified as Pathogenic.

Comment:

The p.R1523* pathogenic mutation (also known as c.4567C>T), located in coding exon 36 of the FBN1 gene, results from a C to T substitution at nucleotide position 4567. This changes the amino acid from an arginine to a stop codon within coding exon 36. THis alteration has been reported in subjects with features of Marfan syndrome and has been reported as de novo (Youil R et al. Hum Mutat, 2000 Jul;16:92-3; Schrijver I et al. Am J Hum Genet, 2002 Aug;71:223-37; Rybczynski M et al. Am J Med Genet A, 2008 Dec;146A:3157-66; Söylen B et al. Clin Genet, 2009 Mar;75:265-70). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Increased frequency of FBN1 truncating and splicing variants in Marfan syndrome patients with aortic events.	Baudhuin LM	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25101912
Marfan syndrome presenting with headache and coincidental ophthalmic artery aneurysm.	Vandersteen AM	BMJ case reports	2013	PMID: 23505274
Identification of the minimal combination of clinical features in probands for efficient mutation detection in the FBN1 gene.	Stheneur C	European journal of human genetics : EJHG	2009	PMID: 19293843
Prevalence of dural ectasia in 63 gene-mutation-positive patients with features of Marfan syndrome type 1 and Loeys-Dietz syndrome and report of 22 novel FBN1 mutations.	Söylen B	Clinical genetics	2009	PMID: 19159394
The spectrum of syndromes and manifestations in individuals screened for suspected Marfan syndrome.	Rybczynski M	American journal of medical genetics. Part A	2008	PMID: 19012347
The importance of mutation detection in Marfan syndrome and Marfan-related disorders: report of 193 FBN1 mutations.	Comeglio P	Human mutation	2007	PMID: 17657824
Premature termination mutations in FBN1: distinct effects on differential allelic expression and on protein and clinical phenotypes.	Schrijver I	American journal of human genetics	2002	PMID: 12068374
Enzymatic mutation detection (EMD) of novel mutations (R565X and R1523X) in the FBN1 gene of patients with Marfan syndrome using T4 endonuclease VII.	Youil R	Human mutation	2000	PMID: 10874320

Text-mined citations for rs397515812 ...

These 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 Nov 30, 2024

ClinVar Genomic variation as it relates to human health

NM_000138.5(FBN1):c.4567C>T (p.Arg1523Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs397515812 ...