NM_000138.5(FBN1):c.4049G>T (p.Cys1350Phe) AND Marfan syndrome

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jan 17, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000663688.3

Allele description [Variation Report for NM_000138.5(FBN1):c.4049G>T (p.Cys1350Phe)]

NM_000138.5(FBN1):c.4049G>T (p.Cys1350Phe)

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.4049G>T (p.Cys1350Phe)

HGVS:

NC_000015.10:g.48474566C>A
NG_008805.2:g.176223G>T
NM_000138.5:c.4049G>TMANE SELECT
NP_000129.3:p.Cys1350Phe
NP_000129.3:p.Cys1350Phe
LRG_778t1:c.4049G>T
LRG_778:g.176223G>T
LRG_778p1:p.Cys1350Phe
NC_000015.9:g.48766763C>A
NM_000138.4:c.4049G>T

Protein change:

C1350F

Links:

dbSNP: rs1555397718

NCBI 1000 Genomes Browser:

rs1555397718

Molecular consequence:

NM_000138.5:c.4049G>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV000787019	Center for Medical Genetics Ghent, University of Ghent	no assertion criteria provided	Likely pathogenic (Nov 7, 2017)	germline	clinical testing
SCV000898694	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 17, 2023)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002025295	Centre of Medical Genetics, University of Antwerp	criteria provided, single submitter (Submitter's publication)	Pathogenic (Mar 1, 2021)	unknown	research	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000787019

Center for Medical Genetics Ghent, University of Ghent

no assertion criteria provided

Likely pathogenic
(Nov 7, 2017)

germline

clinical testing

SCV000898694

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 17, 2023)

de novo

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002025295

Centre of Medical Genetics, University of Antwerp

criteria provided, single submitter

(Submitter's publication)

Pathogenic
(Mar 1, 2021)

unknown

research

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	research
not provided	de novo	unknown	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Center for Medical Genetics Ghent, University of Ghent, SCV000787019.1

#	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 Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago, SCV000898694.3

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

Description

This variant has been reported in the literature in 2 individuals with Marfan syndrome (Baetens 2011 PMID: 21542060; Meester 2022 PMD: 35058154). This variant is absent from gnomAD, but is present in ClinVar (Variation ID: 549204). This variant alters a cysteine residue in a calcium-binding EGF-like domain; cysteines in cbEGF-like domains of the fibrillin-1 protein are established as critical for protein structure and function (Robinson 2006 PMID: 16571647; Faivre 2007 PMID: 17701892). Evolutionary conservation and computational prediction tools strongly support that this variant impacts the encoded protein. In summary, this variant is classified as pathogenic.

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

From Centre of Medical Genetics, University of Antwerp, SCV002025295.1

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

Last Updated: Nov 3, 2024

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