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NM_000138.5(FBN1):c.5788+5G>A AND Marfan syndrome

Germline classification:
Pathogenic/Likely pathogenic (8 submissions)
Last evaluated:
Feb 2, 2022
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:
RCV000035236.14

Allele description [Variation Report for NM_000138.5(FBN1):c.5788+5G>A]

NM_000138.5(FBN1):c.5788+5G>A

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.5788+5G>A
HGVS:
  • NC_000015.10:g.48446701C>T
  • NG_008805.2:g.204088G>A
  • NM_000138.5:c.5788+5G>AMANE SELECT
  • LRG_778t1:c.5788+5G>A
  • LRG_778:g.204088G>A
  • NC_000015.9:g.48738898C>T
  • NM_000138.4:c.5788+5G>A
  • c.5788+5G>A
Nucleotide change:
IVS46+5G-A
Links:
OMIM: 134797.0039; dbSNP: rs193922219
NCBI 1000 Genomes Browser:
rs193922219
Molecular consequence:
  • NM_000138.5:c.5788+5G>A - intron variant - [Sequence Ontology: SO:0001627]
Observations:
2

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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000038200OMIM
no assertion criteria provided
Pathogenic
(Sep 1, 2003)
germlineliterature only

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

SCV000058881Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
criteria provided, single submitter

(LMM Criteria)
Pathogenic
(Feb 17, 2014)
germlineclinical testing

PubMed (14)
[See all records that cite these PMIDs]

SCV000781389Center for Human Genetics, Inc, Center for Human Genetics, Inc
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Nov 1, 2016)
germlineclinical testing

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

SCV000787173Center for Medical Genetics Ghent, University of Ghent
no assertion criteria provided
Likely pathogenic
(Nov 7, 2017)
germlineclinical testing

SCV002025358Centre of Medical Genetics, University of Antwerp
criteria provided, single submitter

(Submitter's publication)
Likely pathogenic
(Mar 1, 2021)
unknownresearch

Citation Link,

SCV002097020Suma Genomics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenicde novoclinical testing

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

SCV002768078Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Feb 2, 2022)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV003915950deCODE genetics, Amgen
no assertion criteria provided
Pathogenic
(Apr 10, 2023)
germlinecase-control

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedde novoyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot provided22not providednot providednot providedclinical testing, literature only
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownyes43not providednot providednot providedresearch
Icelandicgermlineyes2not providednot providednot providednot providedcase-control

Citations

PubMed

Mutant fibrillin-1 monomers lacking EGF-like domains disrupt microfibril assembly and cause severe marfan syndrome.

Liu W, Qian C, Comeau K, Brenn T, Furthmayr H, Francke U.

Hum Mol Genet. 1996 Oct;5(10):1581-7.

PubMed [citation]
PMID:
8894692

Update of the UMD-FBN1 mutation database and creation of an FBN1 polymorphism database.

Collod-Béroud G, Le Bourdelles S, Ades L, Ala-Kokko L, Booms P, Boxer M, Child A, Comeglio P, De Paepe A, Hyland JC, Holman K, Kaitila I, Loeys B, Matyas G, Nuytinck L, Peltonen L, Rantamaki T, Robinson P, Steinmann B, Junien C, Béroud C, Boileau C.

Hum Mutat. 2003 Sep;22(3):199-208. Review.

PubMed [citation]
PMID:
12938084
See all PubMed Citations (19)

Details of each submission

From OMIM, SCV000038200.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (3)

Description

In patients with Marfan syndrome (154700), Nijbroek et al. (1995) and Liu et al. (1996) reported skipping of exon 46 of the FBN1 gene due to a G-to-A transversion at the +5 position of the consensus 5-prime splice site. Collod-Beroud et al. (2003) noted that this mutation was the most frequently recurring mutation to that time, having been reported a total of 9 times.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000058881.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided2not providednot providedclinical testing PubMed (14)

Description

The 5788+5G>A variant has been previously reported in >15 individuals with a cli nical diagnosis or features of Marfan syndrome, and was reported to have occurre d de novo in >10 of these individuals (Nijbroek 1995, Yuan 1999, Loeys 2001, Com eglio 2007, Rommel 2002, Biggin 2004, Arbustini 2005, Sakai 2006, Rand-Hendrikse n 2007, Stheneur 2009, Soylen 2009, Baetens 2011, Aalberts 2014, LMM unpublished data). This variant was absent from large population studies. This variant occu rs in the highly conserved 5' splicing consensus sequence. Nijbroek et al. (1995 ) observed skipping of exon 46 in fibroblasts from an affected individual with t his variant, which is predicted to result in an abnormal protein product. In sum mary, this variant meets our criteria to be classified as pathogenic (http://pcp gm.partners.org/LMM).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided2not provided2not provided

From Center for Human Genetics, Inc, Center for Human Genetics, Inc, SCV000781389.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Center for Medical Genetics Ghent, University of Ghent, SCV000787173.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Centre of Medical Genetics, University of Antwerp, SCV002025358.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided4not providednot providedresearchnot provided

Description

PM2, PS1, PP1, PP4 and PM2, PS1, PP4

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot provided4not provided3not provided

From Suma Genomics, SCV002097020.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1de novoyesnot providednot providednot providednot providednot providednot providednot provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002768078.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with FBN1-related disease. Variants predicted to result in nonsense mediated decay cause loss of function effects and are more commonly associated with severe Marfan syndrome (MIM#154700). Missense variants with both dominant negative and loss of function effects on protein function, are also associated with causing Marfan syndrome and ectopia lentis (MIM#129600) (OMIM, PMID: 29357934). (I) 0107 - This gene is predominantly associated with autosomal dominant disease; however some individuals have been reported with an autosomal recessive form of Marfan syndrome (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity. The genotype-phenotype correlations for this gene are unclear, with the same variant reported in patients with a range of phenotypes (OMIM). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. RT-PCR analysis of cultured fibroblasts from an affected individual showed that the variant causes in-frame skipping of exon 47 and a small amount of abnormally spliced transcripts utilized a cryptic splice donor or a cryptic splice acceptor (PMID: 7611299). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0704 - Another splice variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The c.5788+5G>T variant has been observed in an individual with Marfan syndrome and classified as likely pathogenic (VCGS laboratory). This variant has also been reported twice as a VUS in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with Marfan syndrome (ClinVar, PMID: 7611299, PMID: 24161884). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From deCODE genetics, Amgen, SCV003915950.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1Icelandic2not providednot providedcase-control PubMed (1)

Description

The c.5788+5G>A variant occurred de novo in two siblings (shared de novo) with Marfan syndrome, maternity and paternity confirmed, parental mosaicism assumed. Applied ACMG criteria: PS2, PM2, PP2, PP4, PP5_strong

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided2not providednot providednot provided

Last Updated: Nov 11, 2023