NM_000138.5(FBN1):c.4081T>C (p.Cys1361Arg) AND Marfan syndrome

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Dec 29, 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:: RCV002246009.2

Allele description [Variation Report for NM_000138.5(FBN1):c.4081T>C (p.Cys1361Arg)]

NM_000138.5(FBN1):c.4081T>C (p.Cys1361Arg)

Gene:

FBN1:fibrillin 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

15q21.1

Genomic location:

Preferred name:

NM_000138.5(FBN1):c.4081T>C (p.Cys1361Arg)

Other names:

NM_000138.5(FBN1):c.4081T>C; p.Cys1361Arg

HGVS:

NC_000015.10:g.48474534A>G
NG_008805.2:g.176255T>C
NM_000138.5:c.4081T>CMANE SELECT
NP_000129.3:p.Cys1361Arg
NP_000129.3:p.Cys1361Arg
LRG_778t1:c.4081T>C
LRG_778:g.176255T>C
LRG_778p1:p.Cys1361Arg
NC_000015.9:g.48766731A>G
NC_000015.9:g.48766731A>G
NM_000138.4:c.4081T>C

Protein change:

C1361R

Links:

dbSNP: rs1566906506

NCBI 1000 Genomes Browser:

rs1566906506

Molecular consequence:

NM_000138.5:c.4081T>C - missense variant - [Sequence Ontology: SO:0001583]

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
SCV002025296	Centre of Medical Genetics, University of Antwerp	criteria provided, single submitter (Submitter's publication)	Pathogenic (Mar 1, 2021)	unknown	research	Citation Link,
SCV004218516	ClinGen FBN1 Variant Curation Expert Panel, ClinGen	reviewed by expert panel (Assertion Criteria VCEP FBN1 Version 1)	Likely pathogenic (Dec 29, 2023)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002025296

Centre of Medical Genetics, University of Antwerp

criteria provided, single submitter

(Submitter's publication)

Pathogenic
(Mar 1, 2021)

unknown

research

Citation Link,

SCV004218516

ClinGen FBN1 Variant Curation Expert Panel, ClinGen

reviewed by expert panel

(Assertion Criteria VCEP FBN1 Version 1)

Likely pathogenic
(Dec 29, 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	2	2	not provided	not provided	not provided	research

Details of each submission

From Centre of Medical Genetics, University of Antwerp, SCV002025296.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	research	not provided

Description

PM2, PVS2, 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		2	not provided	2	not provided

From ClinGen FBN1 Variant Curation Expert Panel, ClinGen, SCV004218516.1

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

Description

NM_000138.5 c.4081T>C is a missense variant in FBN1 predicted to cause a substitution of a cysteine by arginine at amino acid 1361 (p.Cys1361Arg). This variant has been identified in at least two individuals with clinical diagnoses of Marfan syndrome and in an individual with a clinical suspicion of Marfan syndrome (PP4, PS4_supporting; PMID: 35058154; CHEO internal data). It is absent from gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/). This variant affects a cysteine residue in a calcium-binding EGF-like domain; cysteine residues are involved in the formation of disulfide bridges which are essential for the protein structure (PM1_strong). Computational prediction tools and conservation analysis support that this variant is likely to impact the protein (PP3; REVEL = 0.920). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). 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: PM1_strong, PS4_supporting, PP2, PP3, PP4, PM2_supporting.

#	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: Mar 5, 2024

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