NM_000138.5(FBN1):c.4016G>C (p.Cys1339Ser) AND Marfan syndrome

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Mar 1, 2021
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:: RCV000035185.6

Allele description [Variation Report for NM_000138.5(FBN1):c.4016G>C (p.Cys1339Ser)]

NM_000138.5(FBN1):c.4016G>C (p.Cys1339Ser)

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.4016G>C (p.Cys1339Ser)

HGVS:

NC_000015.10:g.48474599C>G
NG_008805.2:g.176190G>C
NM_000138.5:c.4016G>CMANE SELECT
NP_000129.3:p.Cys1339Ser
NP_000129.3:p.Cys1339Ser
LRG_778t1:c.4016G>C
LRG_778:g.176190G>C
LRG_778p1:p.Cys1339Ser
NC_000015.9:g.48766796C>G
NM_000138.4:c.4016G>C
c.4016G>C

Protein change:

C1339S

Links:

dbSNP: rs397515798

NCBI 1000 Genomes Browser:

rs397515798

Molecular consequence:

NM_000138.5:c.4016G>C - 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
SCV000058827	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely pathogenic (Dec 6, 2010)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 10486319, 11700157, 24033266
SCV002025293	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

SCV000058827

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Likely pathogenic
(Dec 6, 2010)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV002025293

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	germline	not provided	1	1	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	research

Citations

PubMed

Cysteine substitutions in epidermal growth factor-like domains of fibrillin-1: distinct effects on biochemical and clinical phenotypes.

Schrijver I, Liu W, Brenn T, Furthmayr H, Francke U.

Am J Hum Genet. 1999 Oct;65(4):1007-20.

PubMed [citation]

PMID:: 10486319
PMCID:: PMC1288233

Genotype and phenotype analysis of 171 patients referred for molecular study of the fibrillin-1 gene FBN1 because of suspected Marfan syndrome.

Loeys B, Nuytinck L, Delvaux I, De Bie S, De Paepe A.

Arch Intern Med. 2001 Nov 12;161(20):2447-54.

PubMed [citation]

PMID:: 11700157

See all PubMed Citations (3)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000058827.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (3)

Description

The 4016G>C (Cys1339Ser) variant has not been previously reported in the literat ure or been identified by our laboratory. Another variant at this position, Cys1 339Tyr, has been reported in an individual with Marfan syndrome (Loeys 2001). Th is variant affects a cysteine residue; cysteine substitutions are a common findi ng in individuals with Marfan syndrome (Schrijver 1999). Cystine at amino acid p osition 1339 is highly conserved across evolutionarily distinct species. Therefo re, this variant is likely to be pathogenic.

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

From Centre of Medical Genetics, University of Antwerp, SCV002025293.1

#	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: Dec 24, 2022

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