NM_000138.5(FBN1):c.3632_3634del (p.Phe1211del) AND Marfan syndrome

Germline classification:: Likely pathogenic (3 submissions)
Last evaluated:: Sep 28, 2023
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000663657.2

Allele description [Variation Report for NM_000138.5(FBN1):c.3632_3634del (p.Phe1211del)]

NM_000138.5(FBN1):c.3632_3634del (p.Phe1211del)

Gene:

FBN1:fibrillin 1 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

15q21.1

Genomic location:

Preferred name:

NM_000138.5(FBN1):c.3632_3634del (p.Phe1211del)

Other names:

NM_000138.5(FBN1):c.3632_3634del; p.Phe1211del

HGVS:

NC_000015.10:g.48485454_48485456del
NG_008805.2:g.165335_165337del
NM_000138.5:c.3632_3634delMANE SELECT
NP_000129.3:p.Phe1211del
NP_000129.3:p.Phe1211del
LRG_778t1:c.3632_3634del
LRG_778:g.165335_165337del
LRG_778p1:p.Phe1211del
NC_000015.9:g.48777651_48777653del
NM_000138.4:c.3632_3634del
NM_000138.4:c.3632_3634delTCT

Protein change:

F1211del

Links:

dbSNP: rs1555398404

NCBI 1000 Genomes Browser:

rs1555398404

Molecular consequence:

NM_000138.5:c.3632_3634del - inframe_deletion - [Sequence Ontology: SO:0001822]

Condition(s)

Name:: Marfan syndrome (MFS)
Synonyms:: MARFAN SYNDROME, TYPE I; Marfan syndrome type 1; Marfan's syndrome; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007947; MedGen: C0024796; Orphanet: 284963; Orphanet: 558; OMIM: 154700

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000786984	Center for Medical Genetics Ghent, University of Ghent	no assertion criteria provided	Likely pathogenic (Nov 7, 2017)	germline	clinical testing
SCV002025284	Centre of Medical Genetics, University of Antwerp	criteria provided, single submitter (Submitter's publication)	Likely pathogenic (Mar 1, 2021)	unknown	research	Citation Link,
SCV004037330	ClinGen FBN1 Variant Curation Expert Panel, ClinGen	reviewed by expert panel (Assertion Criteria VCEP FBN1 Version 1)	Likely pathogenic (Sep 28, 2023)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000786984

Center for Medical Genetics Ghent, University of Ghent

no assertion criteria provided

Likely pathogenic
(Nov 7, 2017)

germline

clinical testing

SCV002025284

Centre of Medical Genetics, University of Antwerp

criteria provided, single submitter

(Submitter's publication)

Likely pathogenic
(Mar 1, 2021)

unknown

research

Citation Link,

SCV004037330

ClinGen FBN1 Variant Curation Expert Panel, ClinGen

reviewed by expert panel

(Assertion Criteria VCEP FBN1 Version 1)

Likely pathogenic
(Sep 28, 2023)

germline

curation

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	curation
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	research
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Details of each submission

From Center for Medical Genetics Ghent, University of Ghent, SCV000786984.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Centre of Medical Genetics, University of Antwerp, SCV002025284.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	not provided

Description

PM2, PS1, PP4

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ClinGen FBN1 Variant Curation Expert Panel, ClinGen, SCV004037330.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

The NM_00138 c.3632_3634del is an in-frame deletion in FBN1predicted to cause a deletion of a phenylalanine at position 1211 (p.Phe1211del). This variant was found in a proband with a clinical diagnosis of Marfan syndrome (internal data, University of Ghent) (PP4). This variant was also found in a proband with ectopia lentis and an adverse aortic event and was found to segregate with the disease in two affected family members (internal data, University of Tokyo) (PP1). It has been reported in the literature in two unrelated individuals with ectopia lentis (PMID 19159394, 16222657), in one individual with a clinical diagnosis of Marfan syndrome (Ambry Genetics ClinVarentry) and in two unrelated individuals with thoracic aortic aneurysm and/or dissection (PMID 37042257, 33059708) (PS4). This variant is not present in gnomAD(PM2_sup; https://gnomad.broadinstitute.org/). This variant is located in a non-repeat region in a cbEGF-like domain of the protein (PM4). The variant in FBN1 has been reported three times in ClinVar as likely pathogenic (Variation ID: 549178). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS4, PM4, PM2_Sup, PP1, PP4.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Aug 25, 2024

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